BioPAX pathway converted from "Regulation of TLR by endogenous ligand" in the Reactome database. Regulation of TLR by endogenous ligand Diverse molecules of host-cell origin may serve as endogenous ligands of Toll-like receptors (TLRs) (Erridge C 2010; Piccinini AM & Midwood KS 2010). These molecules are known as damage-associated molecular patterns (DAMPs). DAMPs are immunologically silent in healthy tissues but become active upon tissue damage during both infectious and sterile insult. DAMPs are released from necrotic cells or secreted from activated cells in response to tissue damage to mediate tissue repair by promoting inflammatory responses. However, DAMPs have also been implicated in the pathogenesis of many inflammatory and autoimmune diseases, including rheumatoid arthritis (RA), cancer, and atherosclerosis. The mechanism underlying the switch from DAMPs that initiate controlled tissue repair, to those that mediate chronic, uncontrolled inflammation is still unclear. Recent evidence suggests that an abnormal increase in protein citrullination is involved in disease pathophysiology (Anzilotti C et al. 2010; Sanchez-Pernaute O et al. 2013; Sokolove J et al. 2011; Sharma P et al. 2012). Citrullination is a post-translational modification event mediated by peptidyl-arginine deaminase enzymes which catalyze the deimination of proteins by converting arginine residues into citrullines in the presence of calcium ions. Authored: Shamovsky, Veronica, 2015-09-12 Reviewed: D'Eustachio, Peter, 2015-09-12 Reviewed: Granucci, Francesca, Zanoni, Ivan Edited: Shamovsky, Veronica, 2016-05-10 LEFT-TO-RIGHT HMGB1 release from cells High mobility group box protein 1 (HMGB1) is a ubiquitous nuclear protein that under normal conditions binds and bends DNA and facilitates gene transcription. In response to infection or injury, HMGB1 is actively secreted by innate immune cells and/or released passively by necrotic or damaged cells to function as an alarmin (Andersson U et al. 2000; Scaffidi P et al. 2002; Bonaldi T et al. 2003; Chen G et al. 2004; Lamkanfi M et al. 2010; Beyer C et al. 2012; Yang H et al. 2013). Earlier studies reported that HMGB1 did not diffuse out of cells undergoing apoptosis as HMGB1 was found to be tightly associated with the chromatin in apoptotic cells, even when the cell membrane was permeabilized artificially with detergents (Scaffidi P et al. 2002). This finding is in agreement with the general observation that apoptosis does not promote inflammation. However, further work showed that cells that undergo apoptosis do release HMGB1 (Bell CW et al. 2006; Yamada Y et al. 2011; Spencer DM et al. 2014). In human apoptotic cells (acute myeloid leukemia H60, HeLa, Jurkat T lymphocyte, pancreatic carcinoma PANC1 cell lines) HMGB1 was found to translocate into membrane-bound vesicles which are generated and released by cells during apoptosis (Spencer DM et al. 2014; Schiller M et al 2013). Outside the cell, HMGB1 can serve as an alarmin to activate innate immune responses including chemotaxis and cytokine release in both normal and aberrant immunity (Andersson U et al. 2000; Zetterström CK et al. 2002; Voll RE et al. 2008; Harris HE et al. 2012; Diener KR et al. 2013; Yang H et al. 2013). Authored: Shamovsky, Veronica, 2015-09-12 Reviewed: D'Eustachio, Peter, 2015-09-12 Reviewed: Granucci, Francesca, Zanoni, Ivan Reviewed: Kanneganti, Thirumala-Devi, 2021-02-17 Reviewed: D'Eustachio, Peter, 2021-02-17 Reviewed: Shao, Feng, 2021-04-22 Edited: Shamovsky, Veronica, 2016-05-10 HMGB1 High mobility group protein B1 Amphoterin Reactome DB_ID: 266221 nucleoplasm GENE ONTOLOGY GO:0005654 UniProt:P09429 HMGB1 HMGB1 HMG1 FUNCTION Multifunctional redox sensitive protein with various roles in different cellular compartments. In the nucleus is one of the major chromatin-associated non-histone proteins and acts as a DNA chaperone involved in replication, transcription, chromatin remodeling, V(D)J recombination, DNA repair and genome stability (PubMed:33147444). Proposed to be an universal biosensor for nucleic acids. Promotes host inflammatory response to sterile and infectious signals and is involved in the coordination and integration of innate and adaptive immune responses. In the cytoplasm functions as sensor and/or chaperone for immunogenic nucleic acids implicating the activation of TLR9-mediated immune responses, and mediates autophagy. Acts as danger associated molecular pattern (DAMP) molecule that amplifies immune responses during tissue injury (PubMed:27362237). Released to the extracellular environment can bind DNA, nucleosomes, IL-1 beta, CXCL12, AGER isoform 2/sRAGE, lipopolysaccharide (LPS) and lipoteichoic acid (LTA), and activates cells through engagement of multiple surface receptors. In the extracellular compartment fully reduced HMGB1 (released by necrosis) acts as a chemokine, disulfide HMGB1 (actively secreted) as a cytokine, and sulfonyl HMGB1 (released from apoptotic cells) promotes immunological tolerance (PubMed:23519706, PubMed:23446148, PubMed:23994764, PubMed:25048472). Has proangiogdenic activity (By similarity). May be involved in platelet activation (By similarity). Binds to phosphatidylserine and phosphatidylethanolamide (By similarity). Bound to RAGE mediates signaling for neuronal outgrowth (By similarity). May play a role in accumulation of expanded polyglutamine (polyQ) proteins such as huntingtin (HTT) or TBP (PubMed:23303669, PubMed:25549101).FUNCTION Nuclear functions are attributed to fully reduced HGMB1. Associates with chromatin and binds DNA with a preference to non-canonical DNA structures such as single-stranded DNA, DNA-containing cruciforms or bent structures, supercoiled DNA and ZDNA. Can bent DNA and enhance DNA flexibility by looping thus providing a mechanism to promote activities on various gene promoters by enhancing transcription factor binding and/or bringing distant regulatory sequences into close proximity (PubMed:20123072). May have an enhancing role in nucleotide excision repair (NER) (By similarity). However, effects in NER using in vitro systems have been reported conflictingly (PubMed:19446504, PubMed:19360789). May be involved in mismatch repair (MMR) and base excision repair (BER) pathways (PubMed:15014079, PubMed:16143102, PubMed:17803946). May be involved in double strand break repair such as non-homologous end joining (NHEJ) (By similarity). Involved in V(D)J recombination by acting as a cofactor of the RAG complex: acts by stimulating cleavage and RAG protein binding at the 23 bp spacer of conserved recombination signal sequences (RSS) (By similarity). In vitro can displace histone H1 from highly bent DNA (By similarity). Can restructure the canonical nucleosome leading to relaxation of structural constraints for transcription factor-binding (By similarity). Enhances binding of sterol regulatory element-binding proteins (SREBPs) such as SREBF1 to their cognate DNA sequences and increases their transcriptional activities (By similarity). Facilitates binding of TP53 to DNA (PubMed:23063560). Proposed to be involved in mitochondrial quality control and autophagy in a transcription-dependent fashion implicating HSPB1; however, this function has been questioned (By similarity). Can modulate the activity of the telomerase complex and may be involved in telomere maintenance (By similarity).FUNCTION In the cytoplasm proposed to dissociate the BECN1:BCL2 complex via competitive interaction with BECN1 leading to autophagy activation (PubMed:20819940). Involved in oxidative stress-mediated autophagy (PubMed:21395369). Can protect BECN1 and ATG5 from calpain-mediated cleavage and thus proposed to control their proautophagic and proapoptotic functions and to regulate the extent and severity of inflammation-associated cellular injury (By similarity). In myeloid cells has a protective role against endotoxemia and bacterial infection by promoting autophagy (By similarity). Involved in endosomal translocation and activation of TLR9 in response to CpG-DNA in macrophages (By similarity).FUNCTION In the extracellular compartment (following either active secretion or passive release) involved in regulation of the inflammatory response. Fully reduced HGMB1 (which subsequently gets oxidized after release) in association with CXCL12 mediates the recruitment of inflammatory cells during the initial phase of tissue injury; the CXCL12:HMGB1 complex triggers CXCR4 homodimerization (PubMed:22370717). Induces the migration of monocyte-derived immature dendritic cells and seems to regulate adhesive and migratory functions of neutrophils implicating AGER/RAGE and ITGAM (By similarity). Can bind to various types of DNA and RNA including microbial unmethylated CpG-DNA to enhance the innate immune response to nucleic acids. Proposed to act in promiscuous DNA/RNA sensing which cooperates with subsequent discriminative sensing by specific pattern recognition receptors (By similarity). Promotes extracellular DNA-induced AIM2 inflammasome activation implicating AGER/RAGE (PubMed:24971542). Disulfide HMGB1 binds to transmembrane receptors, such as AGER/RAGE, TLR2, TLR4 and probably TREM1, thus activating their signal transduction pathways. Mediates the release of cytokines/chemokines such as TNF, IL-1, IL-6, IL-8, CCL2, CCL3, CCL4 and CXCL10 (PubMed:12765338, PubMed:18354232, PubMed:19264983, PubMed:20547845, PubMed:24474694). Promotes secretion of interferon-gamma by macrophage-stimulated natural killer (NK) cells in concert with other cytokines like IL-2 or IL-12 (PubMed:15607795). TLR4 is proposed to be the primary receptor promoting macrophage activation and signaling through TLR4 seems to implicate LY96/MD-2 (PubMed:20547845). In bacterial LPS- or LTA-mediated inflammatory responses binds to the endotoxins and transfers them to CD14 for signaling to the respective TLR4:LY96 and TLR2 complexes (PubMed:18354232, PubMed:21660935, PubMed:25660311). Contributes to tumor proliferation by association with ACER/RAGE (By similarity). Can bind to IL1-beta and signals through the IL1R1:IL1RAP receptor complex (PubMed:18250463). Binding to class A CpG activates cytokine production in plasmacytoid dendritic cells implicating TLR9, MYD88 and AGER/RAGE and can activate autoreactive B cells. Via HMGB1-containing chromatin immune complexes may also promote B cell responses to endogenous TLR9 ligands through a B-cell receptor (BCR)-dependent and ACER/RAGE-independent mechanism (By similarity). Inhibits phagocytosis of apoptotic cells by macrophages; the function is dependent on poly-ADP-ribosylation and involves binding to phosphatidylserine on the cell surface of apoptotic cells (By similarity). In adaptive immunity may be involved in enhancing immunity through activation of effector T cells and suppression of regulatory T (TReg) cells (PubMed:15944249, PubMed:22473704). In contrast, without implicating effector or regulatory T-cells, required for tumor infiltration and activation of T-cells expressing the lymphotoxin LTA:LTB heterotrimer thus promoting tumor malignant progression (By similarity). Also reported to limit proliferation of T-cells (By similarity). Released HMGB1:nucleosome complexes formed during apoptosis can signal through TLR2 to induce cytokine production (PubMed:19064698). Involved in induction of immunological tolerance by apoptotic cells; its pro-inflammatory activities when released by apoptotic cells are neutralized by reactive oxygen species (ROS)-dependent oxidation specifically on Cys-106 (PubMed:18631454). During macrophage activation by activated lymphocyte-derived self apoptotic DNA (ALD-DNA) promotes recruitment of ALD-DNA to endosomes (By similarity).FUNCTION (Microbial infection) Critical for entry of human coronaviruses SARS-CoV and SARS-CoV-2, as well as human coronavirus NL63/HCoV-NL63 (PubMed:33147444). Regulates the expression of the pro-viral genes ACE2 and CTSL through chromatin modulation (PubMed:33147444). Required for SARS-CoV-2 ORF3A-induced reticulophagy which induces endoplasmic reticulum stress and inflammatory responses and facilitates viral infection (PubMed:35239449).SUBUNIT Interacts (fully reduced HMGB1) with CXCL12; probably in a 1:2 ratio involving two molecules of CXCL12, each interacting with one HMG box of HMGB1; inhibited by glycyrrhizin (PubMed:22370717). Associates with the TLR4:LY96 receptor complex (PubMed:20547845). Component of the RAG complex composed of core components RAG1 and RAG2, and associated component HMGB1 or HMGB2 (By similarity). Interacts (in cytoplasm upon starvation) with BECN1; inhibits the interaction of BECN1 and BCL2 leading to promotion of autophagy (PubMed:20819940). Interacts with KPNA1; involved in nuclear import (PubMed:17114460). Interacts with SREBF1, TLR2, TLR4, TLR9, PTPRZ1, APEX1, FEN1, POLB, TERT (By similarity). Interacts with IL1B, AGER, MSH2, XPA, XPC, HNF1A, TP53 (PubMed:15014079, PubMed:18250463, PubMed:18160415, PubMed:19446504, PubMed:24474694, PubMed:23063560). Interacts with CD24; the probable CD24:SIGLEC10 complex is proposed to inhibit HGMB1-mediated tissue damage immune response (PubMed:19264983). Interacts with THBD; prevents HGMB1 interaction with ACER/RAGE and inhibits HGMB1 pro-inflammatory activity (PubMed:15841214). Interacts with HAVCR2; impairs HMGB1 binding to B-DNA and likely HMGB1-mediated innate immune response (By similarity). Interacts with XPO1; mediating nuclear export (By similarity). Interacts with HTT (wild-type and mutant HTT with expanded polyglutamine repeat) (PubMed:23303669).SUBUNIT (Microbial infection) Interacts with adenovirus protein pVII; this interaction immobilizes HMGB1 on chromatin, thus preventing its release from cell and subsequent inflammation activation.SUBUNIT (Microbial infection) Interacts with SARS-CoV-2 ORF3A protein; the interaction promotes association of HMGB1 with BECN1, promoting reticulophagy which induces endoplasmic reticulum stress and inflammatory responses and facilitates viral infection.TISSUE SPECIFICITY Ubiquitous. Expressed in platelets (PubMed:11154118).INDUCTION (Microbial infection) Protein levels increase upon infection by human coronavirus SARS-CoV-2.DOMAIN HMG box 2 mediates pro-inflammatory cytokine-stimulating activity and binding to TLR4 (PubMed:12765338, PubMed:20547845). However, not involved in mediating immunogenic activity in the context of apoptosis-induced immune tolerance (PubMed:24474694).DOMAIN The acidic C-terminal domain forms a flexible structure which can reversibly interact intramolecularily with the HMG boxes and modulate binding to DNA and other proteins (PubMed:23063560).PTM Phosphorylated at serine residues. Phosphorylation in both NLS regions is required for cytoplasmic translocation followed by secretion (PubMed:17114460).PTM Acetylated on multiple sites upon stimulation with LPS (PubMed:22801494). Acetylation on lysine residues in the nuclear localization signals (NLS 1 and NLS 2) leads to cytoplasmic localization and subsequent secretion (By similarity). Acetylation on Lys-3 results in preferential binding to DNA ends and impairs DNA bending activity (By similarity).PTM Reduction/oxidation of cysteine residues Cys-23, Cys-45 and Cys-106 and a possible intramolecular disulfide bond involving Cys-23 and Cys-45 give rise to different redox forms with specific functional activities in various cellular compartments: 1- fully reduced HMGB1 (HMGB1C23hC45hC106h), 2- disulfide HMGB1 (HMGB1C23-C45C106h) and 3- sulfonyl HMGB1 (HMGB1C23soC45soC106so).PTM Poly-ADP-ribosylated by PARP1 when secreted following stimulation with LPS (By similarity).PTM In vitro cleavage by CASP1 is liberating a HMG box 1-containing peptide which may mediate immunogenic activity; the peptide antagonizes apoptosis-induced immune tolerance (PubMed:24474694). Can be proteolytically cleaved by a thrombin:thrombomodulin complex; reduces binding to heparin and pro-inflammatory activities (By similarity).PTM Forms covalent cross-links mediated by transglutaminase TGM2, between a glutamine and the epsilon-amino group of a lysine residue, forming homopolymers and heteropolymers.MISCELLANEOUS Proposed to contribute to the pathogenesis of various chronic inflammatory and autoimmune diseases, and cancer. High serum levels are found in several inflammatory events including sepsis, rheumatoid arthritis, artherosclerosis chronic kidney disease, systemic lupus erythematosus (SLE). Seems to be implicated in other diseases characterized by cell death and damage, including diabetes and Alzheimer's disease. Its nucleosome-associated release during secondary necrosis may play a role in SLE (PubMed:19064698). During chemotherapy can mediate regrowth and metastasis of remaining cells in a AGER/RAGE-dependent manner (PubMed:23040637). Purified HMG box 1 acts as a specific antagonist to HGMB1 pro-inflammatory activities (PubMed:14695889).SIMILARITY Belongs to the HMGB family.CAUTION Inconsistent experimental results may reflect the use of inconsistently defined redox forms. A recombinant fully reduced form has been used in a number of experiments. However, the redox states of HMGB1 administered in vivo, may interconvert among each other. Purified HMGB1 by itself has only weak pro-inflammatory activity. Homo sapiens NCBI Taxonomy 9606 UniProt P09429 2 EQUAL 215 EQUAL Reactome Database ID Release 83 266221 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266221 Reactome R-HSA-266221 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-266221.1 Reactome http://www.reactome.org DEF HC23,45-HMGB1 Amphoterin High mobility group protein B1 HMG-1 Differentiation enhancing factor Reactome DB_ID: 6797422 extracellular region GENE ONTOLOGY GO:0005576 23 EQUAL L-cystine (cross-link) MOD MOD:00034 2 EQUAL 215 EQUAL Reactome Database ID Release 83 6797422 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6797422 Reactome R-HSA-6797422 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6797422.2 Reactome Database ID Release 83 6805981 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6805981 Reactome R-HSA-6805981 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6805981.4 23797067 Pubmed 2013 The multifunctional alarmin HMGB1 with roles in the pathophysiology of sepsis and cancer Diener, Kerrilyn R Al-Dasooqi, Noor Lousberg, Erin L Hayball, John D Immunol. Cell Biol. 91:443-50 22344226 Pubmed 2012 The extracellular release of DNA and HMGB1 from Jurkat T cells during in vitro necrotic cell death Beyer, Christian Stearns, Nancy A Giessl, Adreas Distler, Jörg H W Schett, Georg Pisetsky, David S Innate Immun 18:727-37 14532127 Pubmed 2003 Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion Bonaldi, Tiziana Talamo, Fabio Scaffidi, Paola Ferrera, Denise Porto, Annalisa Bachi, Angela Rubartelli, Anna Agresti, Alessandra Bianchi, Marco E EMBO J. 22:5551-60 18300566 Pubmed 2008 High mobility group box 1 in the pathogenesis of inflammatory and autoimmune diseases Voll, Reinhard E Urbonaviciute, Vilma Herrmann, Martin Kalden, Joachim R Isr. Med. Assoc. J. 10:26-8 22293756 Pubmed 2012 HMGB1: a multifunctional alarmin driving autoimmune and inflammatory disease Harris, Helena Erlandsson Andersson, Ulf Pisetsky, David S Nat Rev Rheumatol 8:195-202 16855214 Pubmed 2006 The extracellular release of HMGB1 during apoptotic cell death Bell, Charles W Jiang, Weiwen Reich, Charles F Pisetsky, David S Am. J. Physiol., Cell Physiol. 291:C1318-25 15331624 Pubmed 2004 Bacterial endotoxin stimulates macrophages to release HMGB1 partly through CD14- and TNF-dependent mechanisms Chen, Guoqian Li, Jianhua Ochani, Mahendar Rendon-Mitchell, Beatriz Qiang, Xiaoling Susarla, Seenu Ulloa, Luis Yang, Huan Fan, Saijun Goyert, Sanna M Wang, Ping Tracey, Kevin J Sama, Andrew E Wang, Haichao J. Leukoc. Biol. 76:994-1001 20802146 Pubmed 2010 Inflammasome-dependent release of the alarmin HMGB1 in endotoxemia Lamkanfi, Mohamed Sarkar, Anasuya Vande Walle, L Vitari, Alberto C Amer, Amal O Wewers, Mark D Tracey, Kevin J Kanneganti, Thirumala-Devi Dixit, Vishva M J Immunol 185:4385-92 24846056 Pubmed 2014 The expression of HMGB1 on microparticles from Jurkat and HL-60 cells undergoing apoptosis in vitro Spencer, D M Mobarrez, F Wallén, H Pisetsky, D S Scand. J. Immunol. 80:101-10 12149489 Pubmed 2002 High mobility group box chromosomal protein 1 (HMGB1) is an antibacterial factor produced by the human adenoid Zetterström, Cecilia K Bergman, T Rynnel-Dagöö, Britta Erlandsson Harris, Helena Soder, Olle Andersson, Ulf Boman, Hans G Pediatr. Res. 52:148-54 12110890 Pubmed 2002 Release of chromatin protein HMGB1 by necrotic cells triggers inflammation Scaffidi, Paola Misteli, Tom Bianchi, Marco E Nature 418:191-5 21093407 Pubmed 2011 The release of high mobility group box 1 in apoptosis is triggered by nucleosomal DNA fragmentation Yamada, Yoichiro Fujii, Taku Ishijima, Rei Tachibana, Haruki Yokoue, Natsuki Takasawa, Ryoko Tanuma, Sei-ichi Arch. Biochem. Biophys. 506:188-93 23446148 Pubmed 2013 The many faces of HMGB1: molecular structure-functional activity in inflammation, apoptosis, and chemotaxis Yang, Huan Antoine, Daniel J Andersson, Ulf Tracey, Kevin J J. Leukoc. Biol. 93:865-73 10952726 Pubmed 2000 High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes Andersson, U Wang, H Palmblad, K Aveberger, A C Bloom, O Erlandsson-Harris, H Janson, A Kokkola, R Zhang, M Yang, H Tracey, K J J. Exp. Med. 192:565-70 23194089 Pubmed 2013 During apoptosis HMGB1 is translocated into apoptotic cell-derived membranous vesicles Schiller, Martin Heyder, Petra Ziegler, Saskia Niessen, Anna Claßen, Laura Lauffer, Anna Lorenz, Hanns-Martin Autoimmunity 46:342-6 ACTIVATION Reactome Database ID Release 83 9710340 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9710340 GSDMD pore complex Reactome DB_ID: 9647630 plasma membrane GENE ONTOLOGY GO:0005886 GSDMD oligomer:PIPs Reactome DB_ID: 9647676 Converted from EntitySet in Reactome PIPs PI4P,PI(4,5)P2,PIP3 Reactome DB_ID: 5620974 PIP3 PI(3,4,5)P3 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate Phosphatidylinositol-3,4,5-trisphosphate Reactome DB_ID: 179838 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate(7-) [ChEBI:57836] 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate(7-) 2,3-bis(alkanoyloxy)propyl (1S,2S,3R,4S,5S,6S)-2,6-dihydroxy-3,4,5-tris(phosphonatooxy)cyclohexyl phosphate a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5-trisphosphate) ChEBI CHEBI:57836 Reactome Database ID Release 83 179838 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=179838 Reactome R-ALL-179838 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-179838.4 COMPOUND C05981 additional information MI MI:0361 PIP2 PI(4,5)P2 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate Phosphatidylinositol-4,5-bisphosphate 1-phosphatidyl-1D-myo-inositol 4,5- bisphosphate Reactome DB_ID: 179856 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-) [ChEBI:58456] 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-) a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) 2,3-bis(alkanoyloxy)propyl (1R,2R,3S,4R,5R,6S)-2,3,6-trihydroxy-4,5-bis(phosphonatooxy)cyclohexyl phosphate ChEBI CHEBI:58456 Reactome Database ID Release 83 179856 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=179856 Reactome R-ALL-179856 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-179856.4 COMPOUND C04637 PI4P Phosphatidylinositol 4-phosphate 1-phosphatidyl-1D-myo-inositol 4-phosphate 1-phosphatidyl-1D-myo-inositol 4-phosphates Reactome DB_ID: 392417 1-phosphatidyl-1D-myo-inositol 4-phosphate [ChEBI:17526] 1-phosphatidyl-1D-myo-inositol 4-phosphate ChEBI CHEBI:17526 Reactome Database ID Release 83 392417 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=392417 Reactome R-ALL-392417 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-392417.3 COMPOUND C01277 PubChem Substance 4496 Reactome Database ID Release 83 5620974 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5620974 Reactome R-ALL-5620974 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5620974.2 1 GSDMD_HUMAN GSDMD(1-275) Gasdermin-D(1-275) Gasdermin-D, N-terminal Reactome DB_ID: 9647641 cytosol GENE ONTOLOGY GO:0005829 UniProt:P57764 GSDMD GSDMD DFNA5L GSDMDC1 FKSG10 TISSUE SPECIFICITY Expressed in the suprabasal cells of esophagus, as well as in the isthmus/neck, pit, and gland of the stomach, suggesting preferential expression in differentiating cells.DOMAIN Intramolecular interactions between N- and C-terminal domains mediate autoinhibition in the absence of cleavage by inflammatory caspases CASP1, CASP4 or CASP5 (PubMed:26375003, PubMed:29898893, PubMed:28928145, PubMed:29576317). The linker helix loop inserts into the N-terminal domain (PubMed:28928145). The intrinsic pyroptosis-inducing activity is carried by Gasdermin-D, N-terminal, that is released upon cleavage by inflammatory caspases (PubMed:26375003).PTM Cleavage at Asp-275 by CASP1 (mature and uncleaved precursor forms), CASP4, CASP5 or CASP8 relieves autoinhibition and is sufficient to initiate pyroptosis (PubMed:26375003, PubMed:29898893, PubMed:32109412). Cleavage by CASP1 and CASP4 is not strictly dependent on the consensus cleavage site on GSDMD but depends on an exosite interface on CASP1 that recognizes and binds the Gasdermin-D, C-terminal (GSDMD-CT) part (PubMed:32109412). Cleavage by CASP8 takes place following inactivation of MAP3K7/TAK1 by Yersinia toxin YopJ (By similarity). Cleavage at Asp-87 by CASP3 or CAPS7 inactivates the ability to mediate pyroptosis (PubMed:28392147, PubMed:28045099).SIMILARITY Belongs to the gasdermin family. UniProt P57764 1 EQUAL 275 EQUAL Reactome Database ID Release 83 9647641 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9647641 Reactome R-HSA-9647641 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9647641.1 3 Reactome Database ID Release 83 9647676 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9647676 Reactome R-HSA-9647676 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9647676.1 3 Reactome Database ID Release 83 9647630 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9647630 Reactome R-HSA-9647630 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9647630.1 ACTIVATION Reactome Database ID Release 83 9716491 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9716491 GSDME oligomer:PIP Reactome DB_ID: 9710248 GSDME(1-270) Gasdermin-E (1-270) Gasdermin-E, N-terminal Reactome DB_ID: 9647689 UniProt:O60443 GSDME GSDME DFNA5 ICERE1 TISSUE SPECIFICITY Expressed in cochlea (PubMed:9771715). Low level of expression in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas, with highest expression in placenta (PubMed:9771715).DOMAIN Intramolecular interactions between N- and C-terminal domains may be important for autoinhibition in the absence of activation signal. The intrinsic pyroptosis-inducing activity is carried by the N-terminal domain, that is released upon cleavage by CASP3 or granzyme B (GZMB).PTM Cleavage at Asp-270 by CASP3 (mature and uncleaved precursor forms) or granzyme B (GZMB) relieves autoinhibition and is sufficient to initiate pyroptosis.DISEASE Is a tumor suppressor gene with an important role in colorectal cancer (CRC).SIMILARITY Belongs to the gasdermin family. UniProt O60443 1 EQUAL 270 EQUAL Reactome Database ID Release 83 9647689 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9647689 Reactome R-HSA-9647689 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9647689.1 3 2 Reactome Database ID Release 83 9710248 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9710248 Reactome R-HSA-9710248 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9710248.1 LEFT-TO-RIGHT HMGB1 binds TLR4:MD2 HMGB1 binds TLR4:LY96 High mobility group box protein 1 (HMGB1) is an endogenous molecule that upon stress can be released into the extracellular milieu (Andersson U et al. 2000; Scaffidi P et al. 2002; Bonaldi T et al. 2003; Chen G et al. 2004; Bell CW et al. 2006; Beyer C et al. 2012; Yang H et al. 2013).<p>Using surface plasmon resonance (SPR) analysis recombinant HMGB1 was shown to bind TLR4:LY96(MD2) in a concentration-dependent manner (Yang H et al. 2010; Yang H et al. 2015). The binding required cysteine at the position 106 whereas the C106A HMGB1 mutant failed to bind TLR4:LY96 (Yang H et al. 2010). In addition, C106A and C106S HMGB1 failed to stimulate TNF release in mouse peritoneal macrophages (Yang H et al. 2010). The activity of HMGB1 was found to depend on the redox state of three cysteines at positions 23, 45 and 106 (C23, C45 and C106) (Urbonaviciute V et al. 2009; Venereau E et al. 2012, 2013; Yang H et al. 2012, 2013). Tandem mass spectrometric analysis revealed that the inflammatory activities of HMGB1 required both the formation of an intramolecular disulfide bond between C23 and C45 and the reduced state of C106 (thiol state, C106-SH) (Yang H et al. 2012; Venereau E et al. 2012). Both terminal oxidation of these cysteines to sulfonates (CySO3-) with reactive oxygen species (ROS) and their complete reduction to thiols (CySH) abrogated the cytokine-stimulating activity of HMGB1 in cultured human primary macrophages and mouse macrophage-like RAW 264.7 cells (Yang H et al. 2012; Venereau E et al. 2012). Biosensor-based SPR analysis confirmed that only the disulfide bond (C23-S-S-C45)-containing HMGB1 binds to LY96 (MD2) with high affinity (apparent Kd = 12 nM) regardless of whether LY96 or HMGB1 was immobilized on the sensor chip (Yang H et al. 2015). Moreover, TLR4 and LY96 (MD2) were recruited into CD14-containing lipid rafts of mouse RAW264.7 macrophages after stimulation with HMGB1, suggesting that an optimal HMGB1-dependent TLR4 activation in vitro required the co-receptor CD14 (Kim S et al. 2013). In addition to stimulating cells by direct interaction with innate immune receptors, HMGB1 was found to form immunostimulatory complexes with cytokines and other endogenous and exogenous ligands such as bacterial lipopolysaccharide (LPS) (Youn JH et al. 2008; Wahamaa H et al. 2011; Hreggvidsdottir HS et al. 2009) HMGB1 in complex with LPS, IL1alpha or IL1beta boosted proinflammatory cytokine- and matrix metalloproteinase (MMP3) production in synovial fibroblasts obtained from rheumatoid arthritis (RA) and osteoarthritis (OA) patients (Wahamaa H et al. 2011; He ZW et al. 2013). HMGB1 was reported to associate and amplify the activity of LPS (TLR4 ligand), CpG-ODN (TLR9 ligand) or Pam3CSK4 (TLR1:TLR2 ligand) in a synergistic manner when added to the cultures of human peripheral blood mononuclear cell (PBMC) (Hreggvidsdottir HS et al. 2009). Authored: Shamovsky, Veronica, 2015-09-12 Reviewed: D'Eustachio, Peter, 2015-09-12 Reviewed: Granucci, Francesca, Zanoni, Ivan Edited: Shamovsky, Veronica, 2016-05-10 TLR4:LY96 Reactome DB_ID: 166050 TLR4 2xN4GlycoAsn-TLR4 Reactome DB_ID: 166045 UniProt:O00206 TLR4 TLR4 FUNCTION Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS) (PubMed:27022195). Acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:9237759, PubMed:10835634, PubMed:27022195,PubMed:21393102). Also involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni(2+). Responses triggered by Ni(2+) require non-conserved histidines and are, therefore, species-specific (PubMed:20711192). Both M.tuberculosis HSP70 (dnaK) and HSP65 (groEL-2) act via this protein to stimulate NF-kappa-B expression (PubMed:15809303). In complex with TLR6, promotes sterile inflammation in monocytes/macrophages in response to oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42. In this context, the initial signal is provided by oxLDL- or amyloid-beta 42-binding to CD36. This event induces the formation of a heterodimer of TLR4 and TLR6, which is rapidly internalized and triggers inflammatory response, leading to the NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion. Binds electronegative LDL (LDL(-)) and mediates the cytokine release induced by LDL(-) (PubMed:23880187). Stimulation of monocytes in vitro with M.tuberculosis PstS1 induces p38 MAPK and ERK1/2 activation primarily via TLR2, but also partially via this receptor (PubMed:16622205, PubMed:10835634, PubMed:15809303, PubMed:17478729, PubMed:20037584, PubMed:20711192, PubMed:23880187, PubMed:27022195, PubMed:9237759). Activated by the signaling pathway regulator NMI which acts as damage-associated molecular patterns (DAMPs) in response to cell injury or pathogen invasion, therefore promoting nuclear factor NF-kappa-B activation (PubMed:29038465).SUBUNIT Belongs to the lipopolysaccharide (LPS) receptor, a multi-protein complex containing at least CD14, LY96 and TLR4 (PubMed:11274165). Binding to bacterial LPS leads to homodimerization. Interacts with LY96 via the extracellular domain (PubMed:17803912, PubMed:19252480). Interacts with MYD88 and TIRAP via their respective TIR domains (By similarity). Interacts with TICAM2 (PubMed:14519765, PubMed:25736436). Interacts with NOX4 (PubMed:15356101). Interacts with CNPY3 (By similarity). Interacts with HSP90B1. The interaction with both CNPY3 and HSP90B1 is required for proper folding in the endoplasmic reticulum. Interacts with MAP3K21; this interaction leads to negative regulation of TLR4 signaling (PubMed:21602844). Interacts with CD36, following CD36 stimulation by oxLDL or amyloid-beta 42, and forms a heterodimer with TLR6 (PubMed:20037584). The trimeric complex is internalized and triggers inflammatory response. LYN kinase activity facilitates TLR4-TLR6 heterodimerization and signal initiation. Interacts with TICAM1 in response to LPS in a WDFY1-dependent manner (PubMed:25736436). Interacts with WDFY1 in response to LPS (By similarity). Interacts with SMPDL3B (By similarity). Interacts with CEACAM1; upon lipopolysaccharide stimulation, forms a complex including TLR4 and the phosphorylated form of SYK and CEACAM1, which in turn, recruits PTPN6 that dephosphorylates SYK, reducing the production of reactive oxygen species (ROS) and lysosome disruption, which in turn, reduces the activity of the inflammasome (By similarity). Interacts with RFTN1; the interaction occurs in response to lipopolysaccharide stimulation (PubMed:27022195). Interacts with SCIMP; the interaction occurs in response to lipopolysaccharide stimulation and is enhanced by phosphorylation of SCIMP by LYN (By similarity). This interaction facilitates the phosphorylation of TLR4 by LYN which elicits a selective cytokine response in macrophages (By similarity). Interacts with TRAF3IP3 (PubMed:30573680). Interacts with TREM1; this interaction enhances TLR4-mediated inflammatory response (PubMed:21393102, PubMed:17098818).SUBUNIT (Microbial infection) In case of infection, interacts with uropathogenic E.coli protein TcpC.TISSUE SPECIFICITY Highly expressed in placenta, spleen and peripheral blood leukocytes (PubMed:9435236, PubMed:9237759). Detected in monocytes, macrophages, dendritic cells and several types of T-cells (PubMed:9237759, PubMed:27022195).DOMAIN The TIR domain mediates interaction with NOX4.PTM N-glycosylated. Glycosylation of Asn-526 and Asn-575 seems to be necessary for the expression of TLR4 on the cell surface and the LPS-response. Likewise, mutants lacking two or more of the other N-glycosylation sites were deficient in interaction with LPS.PTM Phosphorylated on tyrosine residues by LYN after binding lipopolysaccharide.POLYMORPHISM Allele TLR4*B (Gly-299, Ile-399) is associated with a blunted response to inhaled LPS.MISCELLANEOUS His-456 and His-458 are found in TLR4 of human and several other primate species and may be responsible for inflammatory responses triggered by nickel (Ni(2+)). Ni(2+) may cross-link the two receptor monomers through specific histidines, triggering the formation of a dimer that structurally resembles that induced by LPS. This process may be the basis for the development of contact allergy to Ni(2+). A mouse model of contact allergy to Ni(2+) in which TLR4-deficient mice expresses human TLR4 has been proposed.SIMILARITY Belongs to the Toll-like receptor family.CAUTION In some plant proteins and in human SARM1, the TIR domain has NAD(+) hydrolase (NADase) activity (PubMed:28334607). However, despite the presence of the catalytic Asp residue, the isolated TIR domain of human TLR4 lacks NADase activity (PubMed:28334607). Based on this, it is unlikely that Toll-like receptors have NADase activity. UniProt O00206 526 EQUAL N4-glycosyl-L-asparagine MOD MOD:00160 575 EQUAL 24 EQUAL 839 EQUAL Reactome Database ID Release 83 166045 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=166045 Reactome R-HSA-166045 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-166045.1 1 Ly-96 2xN4GlycoAsn-LY96 2xN4GlycoAsn-MD2 Lymphocyte antigen 96 ESOP-1 Myeloid differentiation 2 Reactome DB_ID: 166047 UniProt:Q9Y6Y9 LY96 LY96 ESOP1 MD2 FUNCTION Binds bacterial lipopolysaccharide (LPS) (PubMed:17803912, PubMed:17569869). Cooperates with TLR4 in the innate immune response to bacterial lipopolysaccharide (LPS), and with TLR2 in the response to cell wall components from Gram-positive and Gram-negative bacteria (PubMed:11160242, PubMed:11593030). Enhances TLR4-dependent activation of NF-kappa-B (PubMed:10359581). Cells expressing both LY96 and TLR4, but not TLR4 alone, respond to LPS (PubMed:10359581).SUBUNIT Heterogeneous homomer formed from homodimers; disulfide-linked (PubMed:11593030, PubMed:12642668). Belongs to the lipopolysaccharide (LPS) receptor, a multi-protein complex containing at least CD14, LY96 and TLR4 (PubMed:11274165). Binds to the extracellular domains of TLR2 and TLR4 (PubMed:10359581, PubMed:11593030, PubMed:17803912). Ligand binding induces interaction with TLR4 and oligomerization of the complex.PTM N-glycosylated; high-mannose. UniProt Q9Y6Y9 26 EQUAL 114 EQUAL 19 EQUAL 160 EQUAL Reactome Database ID Release 83 166047 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=166047 Reactome R-HSA-166047 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-166047.1 1 Reactome Database ID Release 83 166050 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=166050 Reactome R-HSA-166050 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-166050.1 HMGB1:TLR4:MD2 HC23,45-HMGB1:TLR4:LY96 Reactome DB_ID: 5432869 1 1 Reactome Database ID Release 83 5432869 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5432869 Reactome R-HSA-5432869 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5432869.2 Reactome Database ID Release 83 5432825 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5432825 Reactome R-HSA-5432825 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5432825.2 19564572 Pubmed 2009 The alarmin HMGB1 acts in synergy with endogenous and exogenous danger signals to promote inflammation Hreggvidsdottir, Hulda Sigridur Ostberg, Therese Wähämaa, Heidi Schierbeck, Hanna Aveberger, Ann-Charlotte Klevenvall, Lena Palmblad, Karin Ottosson, Lars Andersson, Ulf Harris, Helena Erlandsson J. Leukoc. Biol. 86:655-62 21871094 Pubmed 2011 High mobility group box protein 1 in complex with lipopolysaccharide or IL-1 promotes an increased inflammatory phenotype in synovial fibroblasts Wähämaa, Heidi Schierbeck, Hanna Hreggvidsdottir, Hulda S Palmblad, Karin Aveberger, Anne-Charlotte Andersson, Ulf Harris, Helena Erlandsson Arthritis Res. Ther. 13:R136 25559892 Pubmed 2015 MD-2 is required for disulfide HMGB1-dependent TLR4 signaling Yang, Huan Wang, Haichao Ju, Zhongliang Ragab, Ahmed A Lundbäck, Peter Long, Wei Valdes-Ferrer, Sergio I He, Mingzhu Pribis, John P Li, Jianhua Lu, Ben Gero, Domokos Szabo, Csaba Antoine, Daniel J Harris, Helena E Golenbock, Doug T Meng, Jianmin Roth, Jesse Chavan, Sangeeta S Andersson, Ulf Billiar, Timothy R Tracey, Kevin J Al-Abed, Yousef J. Exp. Med. 212:5-14 18354232 Pubmed 2008 High mobility group box 1 protein binding to lipopolysaccharide facilitates transfer of lipopolysaccharide to CD14 and enhances lipopolysaccharide-mediated TNF-alpha production in human monocytes Youn, Ju Ho Oh, Young Joo Kim, Eun Sook Choi, Ji Eun Shin, Jeon-Soo J. Immunol. 180:5067-74 24302816 Pubmed 2013 HMGB1 acts in synergy with lipopolysaccharide in activating rheumatoid synovial fibroblasts via p38 MAPK and NF-κB signaling pathways He, Zheng-Wen Qin, Yang-Hua Wang, Zhi-Wei Chen, Yan Shen, Qian Dai, Sheng-Ming Mediators Inflamm. 2013:596716 19811284 Pubmed 2009 Oxidation of the alarmin high-mobility group box 1 protein (HMGB1) during apoptosis Urbonaviciute, Vilma Meister, Silke Fürnrohr, Barbara G Frey, Benjamin Gückel, Eva Schett, Georg Herrmann, Martin Voll, Reinhard E Autoimmunity 42:305-7 23207101 Pubmed 2013 HMGB1 and leukocyte migration during trauma and sterile inflammation Venereau, Emilie Schiraldi, Milena Uguccioni, Mariagrazia Bianchi, Marco E Mol. Immunol. 55:76-82 22869893 Pubmed 2012 Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release Venereau, Emilie Casalgrandi, Maura Schiraldi, Milena Antoine, Daniel J Cattaneo, Angela De Marchis, Francesco Liu, Jaron Antonelli, Antonella Preti, Alessandro Raeli, Lorenzo Shams, Sara Samadi Yang, Huan Varani, Luca Andersson, Ulf Tracey, Kevin J Bachi, Angela Uguccioni, Mariagrazia Bianchi, Marco E J. Exp. Med. 209:1519-28 20547845 Pubmed 2010 A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 and activation of macrophage cytokine release Yang, Huan Hreggvidsdottir, Hulda S Palmblad, Karin Wang, Haichao Ochani, Mahendar Li, Jianhua Lu, Ben Chavan, Sangeeta Rosas-Ballina, Mauricio Al-Abed, Yousef Akira, Shizuo Bierhaus, Angelika Erlandsson-Harris, Helena Andersson, Ulf Tracey, Kevin J Proc. Natl. Acad. Sci. U.S.A. 107:11942-7 16878026 Pubmed 2006 HMGB1 signals through toll-like receptor (TLR) 4 and TLR2 Yu, Man Wang, Haichao Ding, Aihao Golenbock, DT Latz, Eicke Czura, Christopher J Fenton, Matthew J Tracey, Kevin J Yang, Huan Shock 26:174-9 22105604 Pubmed 2012 Redox modification of cysteine residues regulates the cytokine activity of high mobility group box-1 (HMGB1) Yang, Huan Lundbäck, Peter Ottosson, Lars Erlandsson-Harris, Helena Venereau, Emilie Bianchi, Marco E Al-Abed, Yousef Andersson, Ulf Tracey, Kevin J Antoine, Daniel J Mol. Med. 18:250-9 23508573 Pubmed 2013 Signaling of high mobility group box 1 (HMGB1) through toll-like receptor 4 in macrophages requires CD14 Kim, Sodam Kim, Sun Young Pribis, John P Lotze, Michael Mollen, Kevin P Shapiro, Richard Loughran, Patricia Scott, Melanie J Billiar, Timothy R Mol. Med. 19:88-98 LEFT-TO-RIGHT HMGB1 binds LPS High mobility group box 1 (HMGB1) is an ubiquitous nuclear protein that is actively secreted by innate immune cells and/or released passively by necrotic or damaged cells in response to infection or injury (Andersson U et al. 2000; Scaffidi P et al. 2002; Bonaldi T et al. 2003; Chen G et al. 2004; Beyer C et al. 2012; Yang H et al. 2013). Outside the cell, HMGB1 can serve as an alarmin to activate innate immune responses including chemotaxis and cytokine release in both normal and aberrant immunity (Andersson U et al. 2000; Zetterström CK et al. 2002; Voll RE et al. 2008; Harris HE et al. 2012; Diener KR et al. 2013; Yang H et al. 2013).<p> HMGB1 can form immunostimulatory complexes with cytokines and other endogenous and exogenous ligands such as bacterial lipopolysaccharide (LPS) to potentiate proinflammatory response (Youn JH et al. 2008, 2011; Wähämaa H et al. 2011; Hreggvidsdottir HS et al. 2009). The activity of HMGB1 depended on the redox state of three cysteines at positions 23, 45 and 106 (C23, C45 and C106) (Urbonaviciute V et al. 2009; Venereau E et al. 2012, 2013; Yang H et al. 2012, 2013). Tandem mass spectrometric analysis revealed that the inflammatory activities of HMGB1 required both the formation of an intramolecular disulfide bond between C23 and C45 and the reduced state of C106 (thiol state, C106-SH) (Yang H et al. 2012; Venereau E et al. 2012). Both terminal oxidation of these cysteines to sulfonates (CySO3–) with reactive oxygen species (ROS) and their complete reduction to thiols (CySH) abrogated the cytokine-stimulating activity of HMGB1 in cultured human primary macrophages and mouse macrophage-like RAW 264.7 cells (Yang H et al. 2012; Venereau E et al. 2012).<p>HMGB1 binding to LPS facilitated transfer of LPS to CD14 and enhanced TNFalpha production in human peripheral blood mononuclear cells (PBMCs) (Youn JH et al. 2008). HMGB1 in complex with LPS boosted proinflammatory cytokine- and matrix metalloproteinase (MMP3) production in synovial fibroblasts obtained from rheumatoid arthritis (RA) and osteoarthritis (OA) patients (Wähämaa H et al. 2011; He ZW et al. 2013).<p> In addition to its ability to act in a synergy with LPS and other ligands, HMGB1 was shown to stimulate cells by direct interaction with innate immune receptors such as TLR4:LY96 (Yang H et al. 2010; Yang H et al. 2015). Authored: Shamovsky, Veronica, 2015-09-12 Reviewed: D'Eustachio, Peter, 2015-09-12 Reviewed: Granucci, Francesca, Zanoni, Ivan Edited: Shamovsky, Veronica, 2016-05-10 LPS Gram Negative Bacterial Lipopolysaccharide lipopolysaccharide Reactome DB_ID: 166005 lipopolysaccharide [ChEBI:16412] lipopolysaccharide lipopolysaccharides LPS ChEBI CHEBI:16412 Reactome Database ID Release 83 166005 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=166005 Reactome R-ALL-166005 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-166005.4 HC23,45-HMGB1:LPS Reactome DB_ID: 6801229 1 1 Reactome Database ID Release 83 6801229 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6801229 Reactome R-HSA-6801229 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6801229.2 Reactome Database ID Release 83 6804100 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6804100 Reactome R-HSA-6804100 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6804100.2 21660935 Pubmed 2011 Identification of lipopolysaccharide-binding peptide regions within HMGB1 and their effects on subclinical endotoxemia in a mouse model Youn, Ju Ho Kwak, Man Sup Wu, Jie Kim, Eun Sook Ji, Yeounjung Min, Hyun Jin Yoo, Ji-Ho Choi, Ji Eun Cho, Hyun-Soo Shin, Jeon-Soo Eur. J. Immunol. 41:2753-62 LEFT-TO-RIGHT HMGB1 binds LTP Lipoteichoic acid (LTA) is a component of the cell wall of Gram-positive bacteria. LTA induces a toll-like receptor 2 (TLR2)-mediated inflammatory response upon initial binding to coreceptors CD36 and CD14 (Nilsen NJ et al. 2008).<p>High mobility group box protein 1 (HMGB1) is a ubiquitous nuclear protein that under normal conditions binds and bends DNA and facilitates gene transcription. In response to infection or injury, HMGB1 is actively secreted by innate immune cells and/or released passively by necrotic or damaged cells (Andersson U et al. 2000; Scaffidi P et al. 2002; Bonaldi T et al. 2003; Chen G et al. 2004; Beyer C et al. 2012; Yang H et al. 2013). Outside the cell, HMGB1 can serve as an alarmin to activate innate immune responses including chemotaxis and cytokine release in both normal and aberrant immunity (Andersson U et al. 2000; Zetterström CK et al. 2002; Voll RE et al. 2008; Harris HE et al. 2012; Diener KR et al. 2013; Yang H et al. 2013). HMGB1 has been implicated in TLR2-mediated inflammation (Yu M et al. 2006; Park JS et al. 2006). Addition of HMGB1 induced cellular activation and TLR2- and TLR4-mediated NFkappaB-dependent transcription in TLR2- or TLR4-transfected human embryonic kidney-293 (HEK293) cells (Park JS et al. 2006). Mouse Tlr2 was found to associate with immunoprecipitated Hmgb1 from mouse macrophage-like RAW264.7 cell lysates (Park JS et al. 2006). Anti-TLR2 antibodies dose-dependently attenuated HMGB1-induced IL-8 release in TLR2-expressing HEK293 cells and markedly reduced HMGB1 cell surface binding on murine macrophage-like RAW 264.7 cells (Yu M et al. 2006). Moreover, results of ELISA, surface plasmon resonance and native PAGE electrophoretic mobility shift analyses indicated that HMGB1 binds LTA in a concentration-dependent manner and that this binding is inhibited by LBP (Kwak MS et al. 2015). Native PAGE, fluorescence-based transfer and confocal imaging analyses indicated that HMGB1 catalytically disaggregated LTA transfering LTA to CD14. NFkappaB p65 nuclear transmigration, degradation of IkBalpha and reporter assay results demonstrated that NFkappaB activity in HEK293-hTLR2/6 cells was significantly upregulated by a mixture of LTA and soluble CD14 in the presence of HMGB1 (Kwak MS et al. 2015). Furthermore, the production of TNFalpha and IL6 in murine J774A.1 and RAW264.7 cells increased significantly following treatment with a mixture of LTA and HMGB1 compared with treatment with LTA or HMGB1 alone (Kwak MS et al. 2015). Thus, HMGB1 was proposed to play an important role in LTA-mediated inflammation by binding to LTA and transferring LTA to CD14, which is subsequently transferred to TLR2:TLR6 to induce an inflammatory response. Authored: Shamovsky, Veronica, 2015-09-12 Reviewed: D'Eustachio, Peter, 2015-09-12 Reviewed: Granucci, Francesca, Zanoni, Ivan Edited: Shamovsky, Veronica, 2016-05-10 LTA Lipoteichoic acid Reactome DB_ID: 181015 lipoteichoic acid [ChEBI:28640] lipoteichoic acid ChEBI CHEBI:28640 Reactome Database ID Release 83 181015 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181015 Reactome R-ALL-181015 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-181015.4 HC23,45-HMGB1:LTA Reactome DB_ID: 6801223 1 1 Reactome Database ID Release 83 6801223 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6801223 Reactome R-HSA-6801223 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6801223.2 Reactome Database ID Release 83 6804099 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6804099 Reactome R-HSA-6804099 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6804099.2 18458151 Pubmed 2008 Cellular trafficking of lipoteichoic acid and Toll-like receptor 2 in relation to signaling: role of CD14 and CD36 Nilsen, NJ Deininger, S Nonstad, U Skjeldal, F Husebye, H Rodionov, D von Aulock, S Hartung, T Lien, E Bakke, O Espevik, T J Leukoc Biol 84:280-91 25660311 Pubmed 2015 HMGB1 Binds to Lipoteichoic Acid and Enhances TNF-α and IL-6 Production through HMGB1-Mediated Transfer of Lipoteichoic Acid to CD14 and TLR2 Kwak, Man Sup Lim, Mihwa Lee, Yong Joon Lee, Hyun Sook Kim, Young Hun Youn, Ju Ho Choi, Ji Eun Shin, Jeon-Soo J Innate Immun 7:405-16 16267105 Pubmed 2006 High mobility group box 1 protein interacts with multiple Toll-like receptors Park, Jong Sung Gamboni-Robertson, Fabia He, Qianbin Svetkauskaite, Daiva Kim, Jae-Yeol Strassheim, Derek Sohn, Jang-Won Yamada, Shingo Maruyama, Ikuro Banerjee, Anirban Ishizaka, Akitoshi Abraham, Edward Am. J. Physiol., Cell Physiol. 290:C917-24 LEFT-TO-RIGHT SFTPA/SFTPD binds TLR4:MD2 SFTPA/SFTPD binds TLR4:LY96 The hydrophilic pulmonary surfactant proteins SP-A (SFTPA) and SP-D (SFTPD) belong to the C-type lectin family. Members of the C-type lectin family contain an N-terminal collagen-like domain and a C-terminal carbohydrate recognition domain (CRD) (Kishore U et al. 2006). The CRD allows binding to various components, including carbohydrates, phospholipids or charge patterns found on microbes, allergens and dying cells, while the collagen region can interact with receptor molecules present on immune cells in order to initiate clearance mechanisms (Kishore U et al. 2006). SP-A and SP-D are known to bind to a range of microbial pathogens that invade the lungs (Eggleton P & Reid KB 1999; Crouch E & Wright JR 2001; McCormack FX1 & Whitsett JA 2002; Nayak A et al. 2012; Jakel A et al. 2013). SP-A and SP-D form large oligomeric structures to orchestrate the pulmonary innate immune defense by mechanisms that may involve binding and agglutinating pathogens (Kuan SF et al 1992; Griese M & Starosta V 2005; Yamada C et al. 2006; Kishore U et al. 2006; Zhang L et al. 2001). The direct interaction of SP-A with macrophages was shown to promote phagocytosis of Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa (Van Iwaarden JF et al. 1994; Hickman-Davis JM et al. 2002; Ding J et al. 2004; Mikerov AN et al. 2008; Gil M et al. 2009).<p>SP-A and SP-D were found to bind to the recombinant soluble form of extracellular TLR4 domain (sTLR4) and MD2 in a Ca2+ -dependent manner, with involvement of the CRD region (Yamada et al. 2006; Yamazoe M et al. 2008). SP-A was also shown to interact with CD14 (Sano H. et al. 1999). Studies involving gene knock-out mice, murine models of lung hypersensitivity and infection together with functional characterization of cell surface receptors revealed both pro- and anti-inflammatory functions of SP-A and SP-D in the control of lung inflammation in mammals (Guillot L et al. 2002; Madan T et al. 2001, 2005, 2010; Wang JY & Reid KB 2007; Yamada et al. 2006; Yamazoe M et al. 2008; Wang G et al. 2010). Anti-inflammatory effects of SP-A caused inhibition of NF-kB activation and accumulation of inhibitory protein I kappa B-alpha (IkB-alpha) in LPS-challenged alveolar macrophages (AM) (Wu Y et al. 2004). SP-A also inhibited tumor necrosis factor-alpha (TNFalpha) expression induced by smooth LPS but not by rough LPS in the human macrophage-like cell line U937 cells (Sano H. et al. 1999). In addition, SP-A attenuated cell surface binding of smooth LPS and subsequent NF-kB activation in TLR4/MD2 expressing human embryonic kidney (HEK293) cells (Yamada et al. 2006). Like SP-A, SP-D bound to complex of sTLR4:MD2 was found to down regulate a secretion of TNFalpha and activation of NF-kB in LPS-stimulated AM and TLR4/MD-2-transfected HEK293 cells (Yamazoe M et al. 2008). SP-A and SP-D are thought to prevent LPS-elicited inflammatory responses by altering LPS binding to its receptors, TLR4:MD2 or CD14 (Sano H. et al. 1999; Yamada et al. 2006; Yamazoe M et al. 2008). Authored: Shamovsky, Veronica, 2015-09-12 Reviewed: D'Eustachio, Peter, 2015-09-12 Reviewed: Granucci, Francesca, Zanoni, Ivan Edited: Shamovsky, Veronica, 2016-05-10 Converted from EntitySet in Reactome SFTPA oligomer, SFTPD oligomer Reactome DB_ID: 391108 SFTPA oligomer Reactome DB_ID: 391092 Reactome Database ID Release 83 391092 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=391092 Reactome R-HSA-391092 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-391092.3 ChEBI 36080 SFTPD oligomer Reactome DB_ID: 391097 Reactome Database ID Release 83 391097 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=391097 Reactome R-HSA-391097 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-391097.3 ChEBI 36080 Reactome Database ID Release 83 391108 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=391108 Reactome R-HSA-391108 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-391108.2 SP-A/SP-D:TLR4:MD2 Reactome DB_ID: 5432881 1 1 Reactome Database ID Release 83 5432881 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5432881 Reactome R-HSA-5432881 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5432881.2 Reactome Database ID Release 83 5432852 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5432852 Reactome R-HSA-5432852 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5432852.2 23747872 Pubmed 2013 Ligands and receptors of lung surfactant proteins SP-A and SP-D Jakel, Anne Qaseem, Asif S Kishore, U Sim, Robert B Front Biosci (Landmark Ed) 18:1129-40 17981957 Pubmed 2008 Impact of ozone exposure on the phagocytic activity of human surfactant protein A (SP-A) and SP-A variants Mikerov, Anatoly N Umstead, Todd M Gan, Xiaozhuang Huang, Weixiong Guo, Xiaoxuan Wang, Guirong Phelps, David S Floros, Joanna Am. J. Physiol. Lung Cell Mol. Physiol. 294:L121-30 19155216 Pubmed 2009 Surfactant protein A modulates cell surface expression of CR3 on alveolar macrophages and enhances CR3-mediated phagocytosis Gil, Malgorzata McCormack, Francis X Levine, Ann Marie J. Biol. Chem. 284:7495-504 11181646 Pubmed 2001 Surfactant proteins A and D protect mice against pulmonary hypersensitivity induced by Aspergillus fumigatus antigens and allergens Madan, T Kishore, U Singh, M Strong, P Clark, H Hussain, E M Reid, K B Sarma, P U J. Clin. Invest. 107:467-75 10047533 Pubmed 1999 Lung surfactant proteins involved in innate immunity Eggleton, P Reid, K B Curr. Opin. Immunol. 11:28-33 10384140 Pubmed 1999 Pulmonary surfactant protein A modulates the cellular response to smooth and rough lipopolysaccharides by interaction with CD14 Sano, H Sohma, H Muta, T Nomura, S Voelker, D R Kuroki, Y J. Immunol. 163:387-95 16834340 Pubmed 2006 Human pulmonary surfactant protein D binds the extracellular domains of Toll-like receptors 2 and 4 through the carbohydrate recognition domain by a mechanism different from its binding to phosphatidylinositol and lipopolysaccharide Ohya, Madoka Nishitani, Chiaki Sano, Hitomi Yamada, Chieko Mitsuzawa, Hiroaki Shimizu, Takeyuki Saito, Tsuyoshi Smith, Kelly Crouch, Erika Kuroki, Yoshio Biochemistry 45:8657-64 12055204 Pubmed 2002 Cutting edge: the immunostimulatory activity of the lung surfactant protein-A involves Toll-like receptor 4 Guillot, Loïc Balloy, Viviane McCormack, Francis X Golenbock, DT Chignard, Michel Si-Tahar, Mustapha J. Immunol. 168:5989-92 20048345 Pubmed 2010 Humanized SFTPA1 and SFTPA2 transgenic mice reveal functional divergence of SP-A1 and SP-A2: formation of tubular myelin in vivo requires both gene products Wang, Guirong Guo, Xiaoxuan Diangelo, Susan Thomas, Neal J Floros, Joanna J. Biol. Chem. 285:11998-2010 11943658 Pubmed 2002 Killing of Klebsiella pneumoniae by human alveolar macrophages Hickman-Davis, Judy M O'Reilly, Philip Davis, Ian C Peti-Peterdi, Janos Davis, Glenda Young, K Randall Devlin, Robert B Matalon, Sadis Am. J. Physiol. Lung Cell Mol. Physiol. 282:L944-56 18990700 Pubmed 2008 Pulmonary surfactant protein D inhibits lipopolysaccharide (LPS)-induced inflammatory cell responses by altering LPS binding to its receptors Yamazoe, Masami Nishitani, Chiaki Takahashi, Motoko Katoh, Tsuyoshi Ariki, Shigeru Shimizu, Takeyuki Mitsuzawa, Hiroaki Sawada, Kaku Voelker, DR Takahashi, Hiroki Kuroki, Yoshio J. Biol. Chem. 283:35878-88 17544824 Pubmed 2007 The immunoregulatory roles of lung surfactant collectins SP-A, and SP-D, in allergen-induced airway inflammation Wang, Jiu-Yao Reid, Kenneth B M Immunobiology 212:417-25 11278637 Pubmed 2001 Activity of pulmonary surfactant protein-D (SP-D) in vivo is dependent on oligomeric structure Zhang, L Ikegami, M Crouch, E C Korfhagen, T R Whitsett, J A J. Biol. Chem. 276:19214-9 15905537 Pubmed 2005 Susceptibility of mice genetically deficient in the surfactant protein (SP)-A or SP-D gene to pulmonary hypersensitivity induced by antigens and allergens of Aspergillus fumigatus Madan, Taruna Reid, Kenneth B M Singh, Mamta Sarma, P Usha Kishore, U J. Immunol. 174:6943-54 16213021 Pubmed 2006 Surfactant proteins SP-A and SP-D: structure, function and receptors Kishore, U Greenhough, TJ Waters, P Shrive, AK Ghai, R Kamran, MF Bernal, AL Reid, KB Madan, T Chakraborty, T Mol Immunol 43:1293-315 15308505 Pubmed 2004 Accumulation of inhibitory kappaB-alpha as a mechanism contributing to the anti-inflammatory effects of surfactant protein-A Wu, Yingda Adam, Stefanie Hamann, Lutz Heine, Holger Ulmer, Artur J Buwitt-Beckmann, Ute Stamme, Cordula Am. J. Respir. Cell Mol. Biol. 31:587-94 1634623 Pubmed 1992 Interactions of surfactant protein D with bacterial lipopolysaccharides. Surfactant protein D is an Escherichia coli-binding protein in bronchoalveolar lavage Kuan, S F Rust, K Crouch, E J. Clin. Invest. 90:97-106 11181966 Pubmed 2001 Surfactant proteins a and d and pulmonary host defense Crouch, E Wright, J R Annu. Rev. Physiol. 63:521-54 16114131 Pubmed 2005 Role of collectins in innate immunity against aspergillosis Madan, T Kaur, S Saxena, S Singh, M Kishore, U Thiel, S Reid, K B M Sarma, P U Med. Mycol. 43:S155-63 16754682 Pubmed 2006 Surfactant protein A directly interacts with TLR4 and MD-2 and regulates inflammatory cellular response. Importance of supratrimeric oligomerization Yamada, Chieko Sano, Hitomi Shimizu, Takeyuki Mitsuzawa, Hiroaki Nishitani, Chiaki Himi, Tetsuo Kuroki, Yoshio J. Biol. Chem. 281:21771-80 11901176 Pubmed 2002 The pulmonary collectins, SP-A and SP-D, orchestrate innate immunity in the lung McCormack, Francis X Whitsett, Jeffrey A J. Clin. Invest. 109:707-12 15250230 Pubmed 2004 Factors affecting SP-A-mediated phagocytosis in human monocytic cell lines Ding, Jianqiang Umstead, Todd M Floros, Joanna Phelps, David S Respir Med 98:637-50 16130114 Pubmed 2005 Agglutination of Pseudomonas aeruginosa by surfactant protein D Griese, Matthias Starosta, Vitaliy Pediatr. Pulmonol. 40:378-84 20413160 Pubmed 2010 Susceptibility of mice genetically deficient in SP-A or SP-D gene to invasive pulmonary aspergillosis Madan, Taruna Reid, Kenneth B M Clark, Howard Singh, Mamta Nayak, Annapurna Sarma, P Usha Hawgood, Samuel Kishore, U Mol. Immunol. 47:1923-30 22701116 Pubmed 2012 An Insight into the Diverse Roles of Surfactant Proteins, SP-A and SP-D in Innate and Adaptive Immunity Nayak, Annapurna Dodagatta-Marri, Eswari Tsolaki, Anthony George Kishore, U Front Immunol 3:131 7980398 Pubmed 1994 Binding of surfactant protein A to the lipid A moiety of bacterial lipopolysaccharides Van Iwaarden, J F Pikaar, J C Storm, J Brouwer, E Verhoef, J Oosting, R S van Golde, L M Van Strijp, J A Biochem. J. 303:407-11 LEFT-TO-RIGHT SFTPA/SFTPD binds TLR2:TLR1 The lung surfactant proteins SP-A (also known as SFTPA) and SP-D (SFTPD) have been implicated in the regulation of pulmonary host defense and inflammation. SP-A and SP-D were found to bind to the recombinant soluble form of extracellular TLR2 domain (TLR2) via its C-terminal carbohydrate recognition domain (CRD) in a Ca(2+)-dependent manner (Murakami S et al. 2002; Ohya M et al. 2006). SP-A downregulated TLR2-mediated signaling and tumor necrosis factor alpha (TNFalpha) secretion in TLR2-transfected human embryonic kidney 293 (HEK293) cells upon stimulation with TLR2 ligands such as fungal cell surface component zymosan or bacterial peptidoglycan (PGN) (Murakami S et al. 2002; Sato M et al. 2003). Similarly, SP-A significantly reduced PGN-elicited TNFalpha secretion by human leukemic monocyte lymphoma U937 cell line and rat alveolar macrophages (Murakami S et al. 2002). In primary human monocyte-derived macrophage SP-A regulated TLR2 and TLR4 activity by diminishing proinflammatory cytokine production as the result of a decreased phosphorylation of a key regulator of NFkB, IkBalpha. Nuclear translocation of NFkB-p65 (RELA) was also inhibited (Henning LN et al. 2008). SP-A downregulated kinases upstream of IkBalpha by decreasing the phosphorylation of Akt and MAPKs in response to either LPS (TLR4 ligand) or Pam3Cys (TLR2 ligand) (Henning LN et al. 2008). In addition, SP-A upregulated surface protein expression of TLR2 on macrophages, while it did not affect TLR4 surface expression. The increased TLR2 expression is thought to enhance pathogen recognition by TLR2, while SP-A mediated inhibition of TLR signaling may protect from an overreactive inflammatory response (Henning LN et al. 2008). Authored: Shamovsky, Veronica, 2015-09-12 Reviewed: D'Eustachio, Peter, 2015-09-12 Reviewed: Granucci, Francesca, Zanoni, Ivan Edited: Shamovsky, Veronica, 2016-05-10 TLR1:TLR2 Reactome DB_ID: 168946 TLR1 Toll-like receptor 1 TLR1_HUMAN Reactome DB_ID: 6787702 UniProt:Q15399 TLR1 TLR1 KIAA0012 FUNCTION Participates in the innate immune response to microbial agents. Specifically recognizes diacylated and triacylated lipopeptides. Cooperates with TLR2 to mediate the innate immune response to bacterial lipoproteins or lipopeptides (PubMed:21078852). Forms the activation cluster TLR2:TLR1:CD14 in response to triacylated lipopeptides, this cluster triggers signaling from the cell surface and subsequently is targeted to the Golgi in a lipid-raft dependent pathway (PubMed:16880211). Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response.SUBUNIT Interacts (via extracellular domain) with TLR2. TLR2 seems to exist in heterodimers with either TLR1 or TLR6 before stimulation by the ligand. The heterodimers form bigger oligomers in response to their corresponding ligands as well as further heterotypic associations with other receptors such as CD14 and/or CD36 (PubMed:16880211, PubMed:17889651). The activation cluster TLR2:TLR1:CD14 forms in response to triacylated lipopeptides (PubMed:16880211). Binds MYD88 (via TIR domain). Interacts with CNPY3 (By similarity).TISSUE SPECIFICITY Ubiquitous. Highly expressed in spleen, ovary, peripheral blood leukocytes, thymus and small intestine.POLYMORPHISM Genetic variations in TLR1 may influence susceptibility to or protection against contracting leprosy and define the leprosy susceptibility locus 5 [MIM:613223]. Ser-602 is a common allele in Caucasians. It is associated with impaired cell surface expression and receptor function resulting in protection against leprosy.SIMILARITY Belongs to the Toll-like receptor family.CAUTION In some plant proteins and in human SARM1, the TIR domain has NAD(+) hydrolase (NADase) activity (By similarity). However, despite the presence of the catalytic Asp residue, the isolated TIR domain of human TLR4 lacks NADase activity (By similarity). Based on this, it is unlikely that Toll-like receptors have NADase activity. UniProt Q15399 25 EQUAL 786 EQUAL Reactome Database ID Release 83 6787702 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6787702 Reactome R-HSA-6787702 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6787702.1 1 TLR2 Toll Like Receptor 2 Reactome DB_ID: 167992 UniProt:O60603 TLR2 TLR2 TIL4 FUNCTION Cooperates with LY96 to mediate the innate immune response to bacterial lipoproteins and other microbial cell wall components. Cooperates with TLR1 or TLR6 to mediate the innate immune response to bacterial lipoproteins or lipopeptides (PubMed:21078852, PubMed:17889651). Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. May also activate immune cells and promote apoptosis in response to the lipid moiety of lipoproteins (PubMed:10426995, PubMed:10426996). Recognizes mycoplasmal macrophage-activating lipopeptide-2kD (MALP-2), soluble tuberculosis factor (STF), phenol-soluble modulin (PSM) and B.burgdorferi outer surface protein A lipoprotein (OspA-L) cooperatively with TLR6 (PubMed:11441107). Stimulation of monocytes in vitro with M.tuberculosis PstS1 induces p38 MAPK and ERK1/2 activation primarily via this receptor, but also partially via TLR4 (PubMed:16622205). MAPK activation in response to bacterial peptidoglycan also occurs via this receptor (PubMed:16622205). Acts as a receptor for M.tuberculosis lipoproteins LprA, LprG, LpqH and PstS1, some lipoproteins are dependent on other coreceptors (TLR1, CD14 and/or CD36); the lipoproteins act as agonists to modulate antigen presenting cell functions in response to the pathogen (PubMed:19362712). M.tuberculosis HSP70 (dnaK) but not HSP65 (groEL-2) acts via this protein to stimulate NF-kappa-B expression (PubMed:15809303). Recognizes M.tuberculosis major T-antigen EsxA (ESAT-6) which inhibits downstream MYD88-dependent signaling (shown in mouse) (By similarity). Forms activation clusters composed of several receptors depending on the ligand, these clusters trigger signaling from the cell surface and subsequently are targeted to the Golgi in a lipid-raft dependent pathway. Forms the cluster TLR2:TLR6:CD14:CD36 in response to diacylated lipopeptides and TLR2:TLR1:CD14 in response to triacylated lipopeptides (PubMed:16880211). Required for normal uptake of M.tuberculosis, a process that is inhibited by M.tuberculosis LppM (By similarity).SUBUNIT Interacts with LY96, TLR1 and TLR6 (via extracellular domain) (PubMed:17889651). TLR2 seems to exist in heterodimers with either TLR1 or TLR6 before stimulation by the ligand. The heterodimers form bigger oligomers in response to their corresponding ligands as well as further heterotypic associations with other receptors such as CD14 and/or CD36 (PubMed:16880211). Binds MYD88 (via TIR domain). Interacts with TICAM1 (PubMed:12471095). Interacts with CNPY3 (By similarity). Interacts with ATG16L1 (PubMed:23376921). Interacts with PPP1R11 (By similarity). Interacts with TICAM2 (PubMed:25385819).SUBUNIT (Microbial infection) Interacts with M.tuberculosis EsxA.SUBUNIT (Microbial infection) Interacts with M.bovis MPB83.SUBUNIT (Microbial infection) Interacts with Staphylococcus aureus protein SSL5.TISSUE SPECIFICITY Highly expressed in peripheral blood leukocytes, in particular in monocytes, in bone marrow, lymph node and in spleen. Also detected in lung and in fetal liver. Levels are low in other tissues.INDUCTION (Microbial infection) In macrophages, induced by SARS-CoV-2 infection.DOMAIN Ester-bound lipid substrates are bound through a crevice formed between the LRR 11 and LRR 12.DOMAIN The ATG16L1-binding motif mediates interaction with ATG16L1.PTM Glycosylation of Asn-442 is critical for secretion of the N-terminal ectodomain of TLR2.PTM Ubiquitinated at Lys-754 by PPP1R11, leading to its degradation (PubMed:27805901). Deubiquitinated by USP2 (By similarity).POLYMORPHISM Genetic variations in TLR2 are associated with susceptibility to leprosy [MIM:246300]. Leprosy is a chronic disease associated with depressed cellular (but not humoral) immunity, the bacterium requires a lower temperature than 37 degrees Celsius and thrives particularly in peripheral Schwann cells and macrophages. The Trp-677 polymorphism in the intracellular domain of TLR2 has a role in susceptibility to lepromatous leprosy. Wild-type TLR2 mediates CD14-enhanced Mycobacterium leprae-dependent activation of NFKB1, but TLR2 containing the Trp-677 polymorphism did not. The impaired function of the Trp-677 polymorphism provides a molecular mechanism for the poor cellular immune response associated with lepromatous leprosy.SIMILARITY Belongs to the Toll-like receptor family.CAUTION In some plant proteins and in human SARM1, the TIR domain has NAD(+) hydrolase (NADase) activity (By similarity). However, despite the presence of the catalytic Asp residue, the isolated TIR domain of human TLR4 lacks NADase activity (By similarity). Based on this, it is unlikely that Toll-like receptors have NADase activity. UniProt O60603 19 EQUAL 784 EQUAL Reactome Database ID Release 83 167992 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=167992 Reactome R-HSA-167992 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-167992.1 1 Reactome Database ID Release 83 168946 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168946 Reactome R-HSA-168946 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168946.2 ComplexPortal CPX-893 SFTPA/SFTPD:TLR2:TLR1 Reactome DB_ID: 5432872 1 1 Reactome Database ID Release 83 5432872 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5432872 Reactome R-HSA-5432872 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5432872.2 Reactome Database ID Release 83 5432814 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5432814 Reactome R-HSA-5432814 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5432814.2 11724772 Pubmed 2002 Surfactant protein A inhibits peptidoglycan-induced tumor necrosis factor-alpha secretion in U937 cells and alveolar macrophages by direct interaction with toll-like receptor 2 Murakami, Seiji Iwaki, Daisuke Mitsuzawa, Hiroaki Sano, Hitomi Takahashi, Hiroki Voelker, DR Akino, Toyoaki Kuroki, Yoshio J. Biol. Chem. 277:6830-7 18523248 Pubmed 2008 Pulmonary surfactant protein A regulates TLR expression and activity in human macrophages Henning, Lisa N Azad, Abul K Parsa, Kishore V L Crowther, Joy E Tridandapani, Susheela Schlesinger, Larry S J. Immunol. 180:7847-58 12817025 Pubmed 2003 Direct binding of Toll-like receptor 2 to zymosan, and zymosan-induced NF-kappa B activation and TNF-alpha secretion are down-regulated by lung collectin surfactant protein A Sato, Morihito Sano, Hitomi Iwaki, Daisuke Kudo, Kazumi Konishi, Masanori Takahashi, Hiroki Takahashi, Toru Imaizumi, Hitoshi Asai, Yasufumi Kuroki, Yoshio J. Immunol. 171:417-25 LEFT-TO-RIGHT Calprotectin binds TLR4:MD2 S100A8:S100A9 binds TLR4:LY96 S100A8 (also known as MRP8) and S100A9 (MRP14) are Ca(2+)-binding proteins that are associated with acute and chronic inflammation and cancer (Ehrchen JM et al. 2009; De Jong HK et al. 2015). S100A8 & S100A9 have been identified as important damage-associated molecular patterns (DAMPs) recognized by TLR4 (Foell D et al. 2007; Vogl t et al. 2007; 2012; Kang JH et al. 2015). Surface plasmon resonance studies showed that S100A8 can directly interact with TLR4:MD2 complex with Kd of 1.1-2.5 x 10e-8 M ((Vogl T et al. 2007). Human embryonic kidney cells stably transfected with TLR4,CD14 and MD2 demonstrated a strong induction of proinflammatory cytokines like TNFalpha and IL8 after stimulation with LPS as well as with S100A8 (Vogl T et al. 2007). Induction of NFkB responses by S100A9 in human monocytic THP-1 cell line and mouse bone marrow-derived dendritic cells was TLR4-dependent (Riva M et al. 2012). Moreover, induction of MUC5AC mRNA and protein in normal human bronchial epithelial cells as well as NCI-H292 lung carcinoma cells occurred in a dose-dependent manner trough TLR4 signaling pathway (Kang JH et al. 2015). In addition, S100A8:S100A9 was reported to regulate cell survival of human neutrophils through a signaling mechanism involving an activation of MEK:ERK1 via TLR4 (Atallah M et al. 2012). In experimental mouse models the proinflammatory and TLR4-dependent activities of S100A8:S100AA9 were further confirmed (Vogl t et al. 2007; Loser K et al. 2010; Kuipers MT et al. 2013; Deguchi A et al. 2015).<p>S100A8 & S100A9 are constitutively expressed in neutrophils, myeloid-derived dendritic cells, platelets, osteoclasts and hypertrophic chondrocytes (Hessian PA et al. 1993; Kumar A et al. 2003; Healy AM et al. 2006; Schelbergen RF et al 2012). In contrast, these molecules are induced under inflammatory stimuli in monocytes/macrophages, microvascular endothelial cells, keratinocytes and fibroblasts (Hessian PA et al. 1993; Eckert RL et al. 2004; Viemann D et al. 2005; McCormick MM et al. 2005; Hsu K et al. 2005). S100A8 & S100A9 tend to form homodimers and heterodimers (Kumar RK et al. 2001; Riva M et al. 2013; Korndorfer IP et al. 2007). The heterodimeric S100A8:S100A9 complex is termed calprotectin and is considered as the predominantly occurring form. In response to stress S100A8:S100A9 is primarily released from activated or necrotic neutrophils to extracellular milieu where it functions as an innate immune mediator of infection, autoimmunity, and cancer (Ehrchen JM et al. 2009; Rammes A et al. 1997; Frosch M et al. 2000; Loser K et al. 2010). <p>S100A8 and S100A9 protein levels were elevated in patients with a wide range of inflammatory diseases, including rheumatoid arthritis, juvenile idiopathic arthritis, inflammatory bowel disease, acute lung inflammation, sepsis and vasculitis (Ehrchen JM et al. 2009; van Zoelen MA et al. 2009; Vogl T et a;. 2012; Holzinger D et al. 2012; Rahman MT et al. 2014; Anink J et al. 2015. Increased S100A8 and S100A9 serum levels have been also identified as independent risk predictors for various cardiovascular diseases such as acute coronary syndrome and myocardial infarction (Yonekawa K et al. 2011; Cotoi OS et al. 2014; Larsen SB et al. 2015). Authored: Shamovsky, Veronica, 2015-09-12 Reviewed: D'Eustachio, Peter, 2015-09-12 Reviewed: Granucci, Francesca, Zanoni, Ivan Edited: Shamovsky, Veronica, 2016-05-10 calprotectin S100A8:S100A9 Reactome DB_ID: 5432834 S100A8 calgranulin-A calprotectin L1L subunit cystic fibrosis antigen Reactome DB_ID: 5432846 UniProt:P05109 S100A8 S100A8 CAGA CFAG MRP8 FUNCTION S100A8 is a calcium- and zinc-binding protein which plays a prominent role in the regulation of inflammatory processes and immune response. It can induce neutrophil chemotaxis and adhesion. Predominantly found as calprotectin (S100A8/A9) which has a wide plethora of intra- and extracellular functions. The intracellular functions include: facilitating leukocyte arachidonic acid trafficking and metabolism, modulation of the tubulin-dependent cytoskeleton during migration of phagocytes and activation of the neutrophilic NADPH-oxidase. Activates NADPH-oxidase by facilitating the enzyme complex assembly at the cell membrane, transferring arachidonic acid, an essential cofactor, to the enzyme complex and S100A8 contributes to the enzyme assembly by directly binding to NCF2/P67PHOX. The extracellular functions involve pro-inflammatory, antimicrobial, oxidant-scavenging and apoptosis-inducing activities. Its pro-inflammatory activity includes recruitment of leukocytes, promotion of cytokine and chemokine production, and regulation of leukocyte adhesion and migration. Acts as an alarmin or a danger associated molecular pattern (DAMP) molecule and stimulates innate immune cells via binding to pattern recognition receptors such as Toll-like receptor 4 (TLR4) and receptor for advanced glycation endproducts (AGER). Binding to TLR4 and AGER activates the MAP-kinase and NF-kappa-B signaling pathways resulting in the amplification of the pro-inflammatory cascade. Has antimicrobial activity towards bacteria and fungi and exerts its antimicrobial activity probably via chelation of Zn(2+) which is essential for microbial growth. Can induce cell death via autophagy and apoptosis and this occurs through the cross-talk of mitochondria and lysosomes via reactive oxygen species (ROS) and the process involves BNIP3. Can regulate neutrophil number and apoptosis by an anti-apoptotic effect; regulates cell survival via ITGAM/ITGB and TLR4 and a signaling mechanism involving MEK-ERK. Its role as an oxidant scavenger has a protective role in preventing exaggerated tissue damage by scavenging oxidants. Can act as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread. The iNOS-S100A8/A9 transnitrosylase complex directs selective inflammatory stimulus-dependent S-nitrosylation of GAPDH and probably multiple targets such as ANXA5, EZR, MSN and VIM by recognizing a [IL]-x-C-x-x-[DE] motif; S100A8 seems to contribute to S-nitrosylation site selectivity.FUNCTION (Microbial infection) Upon infection by human coronavirus SARS-CoV-2, may induce expansion of aberrant immature neutrophils in a TLR4-dependent manner.ACTIVITY REGULATION Calprotectin (S100A8/A9) activity on TLR4 signaling is inhibited by paquinimod.SUBUNIT Homodimer. Preferentially exists as a heterodimer or heterotetramer with S100A9 known as calprotectin (S100A8/A9). S100A8 interacts with AGER, ATP2A2 and with the heterodimeric complex formed by TLR4 and LY96 (By similarity). Interacts with GAPDH. Calprotectin (S100A8/9) interacts with CEACAM3 and tubulin filaments in a calcium-dependent manner. Heterotetrameric calprotectin (S100A8/A9) interacts with ANXA6 and associates with tubulin filaments in activated monocytes. S100A8 and calprotectin (S100A8/9) interact with NCF2/P67PHOX, RAC1 and RAC2. Calprotectin (S100A8/9) interacts with CYBA and CYBB. Calprotectin (S100A8/9) interacts with NOS2 to form the iNOS-S100A8/A9 transnitrosylase complex; induced by LDL(ox) (PubMed:25417112).TISSUE SPECIFICITY Calprotectin (S100A8/9) is predominantly expressed in myeloid cells. Except for inflammatory conditions, the expression is restricted to a specific stage of myeloid differentiation since both proteins are expressed in circulating neutrophils and monocytes but are absent in normal tissue macrophages and lymphocytes. Under chronic inflammatory conditions, such as psoriasis and malignant disorders, also expressed in the epidermis. Found in high concentrations at local sites of inflammation or in the serum of patients with inflammatory diseases such as rheumatoid, cystic fibrosis, inflammatory bowel disease, Crohn's disease, giant cell arteritis, cystic fibrosis, Sjogren's syndrome, systemic lupus erythematosus, and progressive systemic sclerosis. Involved in the formation and deposition of amyloids in the aging prostate known as corpora amylacea inclusions. Strongly up-regulated in many tumors, including gastric, esophageal, colon, pancreatic, bladder, ovarian, thyroid, breast and skin cancers.INDUCTION (Microbial infection) Expression is highly induced in CD14(+) monocytes, neutrophils, and developing neutrophils of patients infected by SARS-COV-2.MISCELLANEOUS Binds two calcium ions per molecule with an affinity similar to that of the S100 proteins.SIMILARITY Belongs to the S-100 family. UniProt P05109 1 EQUAL 93 EQUAL Reactome Database ID Release 83 5432846 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5432846 Reactome R-HSA-5432846 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5432846.2 1 S100A9 calgranulin-B calprotectin L1H subunit S100 calcium-binding protein A9 Reactome DB_ID: 5432857 UniProt:P06702 S100A9 S100A9 CAGB CFAG MRP14 FUNCTION S100A9 is a calcium- and zinc-binding protein which plays a prominent role in the regulation of inflammatory processes and immune response (PubMed:12626582, PubMed:15331440, PubMed:20103766, PubMed:8423249, PubMed:16258195, PubMed:19122197, PubMed:21325622). It can induce neutrophil chemotaxis, adhesion, can increase the bactericidal activity of neutrophils by promoting phagocytosis via activation of SYK, PI3K/AKT, and ERK1/2 and can induce degranulation of neutrophils by a MAPK-dependent mechanism (PubMed:12626582, PubMed:15331440, PubMed:20103766). Predominantly found as calprotectin (S100A8/A9) which has a wide plethora of intra- and extracellular functions (PubMed:8423249, PubMed:16258195, PubMed:19122197). The intracellular functions include: facilitating leukocyte arachidonic acid trafficking and metabolism, modulation of the tubulin-dependent cytoskeleton during migration of phagocytes and activation of the neutrophilic NADPH-oxidase (PubMed:15331440, PubMed:21325622). Activates NADPH-oxidase by facilitating the enzyme complex assembly at the cell membrane, transferring arachidonic acid, an essential cofactor, to the enzyme complex and S100A8 contributes to the enzyme assembly by directly binding to NCF2/P67PHOX (PubMed:15642721, PubMed:22808130). The extracellular functions involve pro-inflammatory, antimicrobial, oxidant-scavenging and apoptosis-inducing activities (PubMed:8423249, PubMed:19534726). Its pro-inflammatory activity includes recruitment of leukocytes, promotion of cytokine and chemokine production, and regulation of leukocyte adhesion and migration (PubMed:15598812, PubMed:21487906). Acts as an alarmin or a danger associated molecular pattern (DAMP) molecule and stimulates innate immune cells via binding to pattern recognition receptors such as Toll-like receptor 4 (TLR4) and receptor for advanced glycation endproducts (AGER) (PubMed:19402754). Binding to TLR4 and AGER activates the MAP-kinase and NF-kappa-B signaling pathways resulting in the amplification of the pro-inflammatory cascade (PubMed:19402754, PubMed:22804476). Has antimicrobial activity towards bacteria and fungi and exerts its antimicrobial activity probably via chelation of Zn(2+) which is essential for microbial growth (PubMed:19087201). Can induce cell death via autophagy and apoptosis and this occurs through the cross-talk of mitochondria and lysosomes via reactive oxygen species (ROS) and the process involves BNIP3 (PubMed:19935772). Can regulate neutrophil number and apoptosis by an anti-apoptotic effect; regulates cell survival via ITGAM/ITGB and TLR4 and a signaling mechanism involving MEK-ERK (PubMed:22363402). Its role as an oxidant scavenger has a protective role in preventing exaggerated tissue damage by scavenging oxidants (PubMed:22489132, PubMed:21912088). Can act as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread (PubMed:16258195). Has transnitrosylase activity; in oxidatively-modified low-densitity lipoprotein (LDL(ox))-induced S-nitrosylation of GAPDH on 'Cys-247' proposed to transfer the NO moiety from NOS2/iNOS to GAPDH via its own S-nitrosylated Cys-3 (PubMed:25417112). The iNOS-S100A8/A9 transnitrosylase complex is proposed to also direct selective inflammatory stimulus-dependent S-nitrosylation of multiple targets such as ANXA5, EZR, MSN and VIM by recognizing a [IL]-x-C-x-x-[DE] motif (PubMed:25417112).SUBUNIT Homodimer (PubMed:11851337, PubMed:16258195). Preferentially exists as a heterodimer or heterotetramer with S100A8 known as calprotectin (S100A8/A9) (PubMed:16258195, PubMed:17553524, PubMed:19087201, PubMed:19122197, PubMed:8423249, PubMed:9083090, PubMed:25417112). S100A9 interacts with ATP2A2 (By similarity). S100A9 interacts with AGER, and with the heterodimeric complex formed by TLR4 and LY96 in the presence of calcium and/or zinc ions (PubMed:19402754). S100A9 binds quinoline-3-carboxamides in the presence of calcium and/or zinc ions (PubMed:19402754). S100A9 interacts with amyloid-beta protein 40 (PubMed:22457725). Calprotectin (S100A8/9) interacts with CEACAM3 and tubulin filaments in a calcium-dependent manner (PubMed:11708798). Heterotetrameric calprotectin (S100A8/A9) interacts with ANXA6 and associates with tubulin filaments in activated monocytes (PubMed:18786929). Calprotectin (S100A8/9) interacts with NCF2/P67PHOX, RAC1, RAC2, CYBA and CYBB (PubMed:15642721, PubMed:22808130). Calprotectin (S100A8/9) interacts with NOS2 to form the iNOS-S100A8/A9 transnitrosylase complex; induced by LDL(ox) (PubMed:25417112).TISSUE SPECIFICITY Calprotectin (S100A8/9) is predominantly expressed in myeloid cells. Except for inflammatory conditions, the expression is restricted to a specific stage of myeloid differentiation since both proteins are expressed in circulating neutrophils and monocytes but are absent in normal tissue macrophages and lymphocytes. Under chronic inflammatory conditions, such as psoriasis and malignant disorders, also expressed in the epidermis. Found in high concentrations at local sites of inflammation or in the serum of patients with inflammatory diseases such as rheumatoid, cystic fibrosis, inflammatory bowel disease, Crohn's disease, giant cell arteritis, cystic fibrosis, Sjogren's syndrome, systemic lupus erythematosus, and progressive systemic sclerosis. Involved in the formation and deposition of amyloids in the aging prostate known as corpora amylacea inclusions. Strongly up-regulated in many tumors, including gastric, esophageal, colon, pancreatic, bladder, ovarian, thyroid, breast and skin cancers.PTM Phosphorylated. Phosphorylation inhibits activation of tubulin polymerization.PTM S-nitrosylation of Cys-3 is implicated in LDL(ox)-induced S-nitrosylation of GAPDH at 'Cys-247' through a transnitrosylase mechanism involving a iNOS-S100A8/9 complex (PubMed:25417112).PTM Methylation at His-105 by METTL9 reduces zinc-binding without affecting heterodimerization with S100A8.SIMILARITY Belongs to the S-100 family. UniProt P06702 2 EQUAL 114 EQUAL Reactome Database ID Release 83 5432857 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5432857 Reactome R-HSA-5432857 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5432857.2 1 Reactome Database ID Release 83 5432834 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5432834 Reactome R-HSA-5432834 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5432834.3 TLR4:MD2:calprotectin TLR4:LY96:S100A8:S100A9 Reactome DB_ID: 5432865 1 1 Reactome Database ID Release 83 5432865 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5432865 Reactome R-HSA-5432865 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5432865.2 Reactome Database ID Release 83 5432849 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5432849 Reactome R-HSA-5432849 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5432849.2 25860480 Pubmed 2015 Expression and function of S100A8/A9 (calprotectin) in human typhoid fever and the murine Salmonella model De Jong, Hanna K Achouiti, Ahmed Koh, Gavin C K W Parry, Christopher M Baker, Stephen Faiz, Mohammed Abul van Dissel, Jaap T Vollaard, Albert M van Leeuwen, Ester M M Roelofs, Joris J T H de Vos, Alex F Roth, Johannes van der Poll, Tom Vogl, Thomas Wiersinga, Willem Joost PLoS Negl Trop Dis 9:e0003663 10728757 Pubmed 2000 Myeloid-related proteins 8 and 14 are specifically secreted during interaction of phagocytes and activated endothelium and are useful markers for monitoring disease activity in pauciarticular-onset juvenile rheumatoid arthritis Frosch, M Strey, A Vogl, T Wulffraat, N M Kuis, W Sunderkötter, C Harms, E Sorg, C Roth, J Arthritis Rheum. 43:628-37 14555857 Pubmed 2003 Interleukin-10 influences the expression of MRP8 and MRP14 in human dendritic cells Kumar, Anita Steinkasserer, Alexander Berchtold, Susanne Int. Arch. Allergy Immunol. 132:40-7 11435486 Pubmed 2001 Dimeric S100A8 in human neutrophils is diminished after phagocytosis Kumar, R K Yang, Z Bilson, S Thliveris, S Cooke, B E Geczy, C L J. Leukoc. Biol. 70:59-64 15699168 Pubmed 2005 Regulation of S100A8 by glucocorticoids Hsu, Kenneth Passey, Robert J Endoh, Yasumi Rahimi, Farid Youssef, Peter Yen, Tina Geczy, Carolyn L J. Immunol. 174:2318-26 17553524 Pubmed 2007 The crystal structure of the human (S100A8/S100A9)2 heterotetramer, calprotectin, illustrates how conformational changes of interacting alpha-helices can determine specific association of two EF-hand proteins Korndörfer, Ingo P Brueckner, Florian Skerra, Arne J. Mol. Biol. 370:887-98 9083090 Pubmed 1997 Myeloid-related protein (MRP) 8 and MRP14, calcium-binding proteins of the S100 family, are secreted by activated monocytes via a novel, tubulin-dependent pathway Rammes, A Roth, J Goebeler, M Klempt, M Hartmann, M Sorg, C J. Biol. Chem. 272:9496-502 15598812 Pubmed 2005 Myeloid-related proteins 8 and 14 induce a specific inflammatory response in human microvascular endothelial cells Viemann, Dorothee Strey, Anke Janning, Annette Jurk, Kerstin Klimmek, Kerstin Vogl, Thomas Hirono, Keiichi Ichida, Fukiko Foell, Dirk Kehrel, Beate Gerke, Volker Sorg, Clemens Roth, Johannes Blood 105:2955-62 15191538 Pubmed 2004 S100 proteins in the epidermis Eckert, Richard L Broome, Ann-Marie Ruse, Monica Robinson, Nancy Ryan, D Lee, Kathleen J. Invest. Dermatol. 123:23-33 22267331 Pubmed 2012 The Toll-like receptor 4 agonist MRP8/14 protein complex is a sensitive indicator for disease activity and predicts relapses in systemic-onset juvenile idiopathic arthritis Holzinger, Dirk Frosch, Michael Kastrup, Astrid Prince, Femke H M Otten, Marieke H Van Suijlekom-Smit, Lisette W A ten Cate, Rebecca Hoppenreijs, Esther P A H Hansmann, Sandra Moncrieffe, Halima Ursu, Simona Wedderburn, Lucy R Roth, Johannes Foell, Dirk Wittkowski, Helmut Ann. Rheum. Dis. 71:974-80 25970343 Pubmed 2015 Calprotectin and platelet aggregation in patients with stable coronary artery disease Larsen, Sanne Bøjet Grove, Erik Lerkevang Pareek, Manan Kristensen, Steen Dalby Hvas, Anne-Mette PLoS ONE 10:e0125992 24231443 Pubmed 2014 TLR4 endogenous ligand MRP8/14 level in enthesitis-related arthritis and its association with disease activity and TLR4 expression Rahman, Mujeeb T Myles, Arpita Gaur, Priyanka Misra, Ramnath Aggarwal, Amita Rheumatology (Oxford) 53:270-4 19762566 Pubmed 2009 Expression and role of myeloid-related protein-14 in clinical and experimental sepsis van Zoelen, Marieke A D Vogl, Thomas Foell, Dirk Van Veen, Suzanne Q van Till, Jan W O Florquin, Sandrine Tanck, Michael W Wittebole, Xavier Laterre, Pierre-François Boermeester, Marja A Roth, Johannes van der Poll, Tom Am. J. Respir. Crit. Care Med. 180:1098-106 22363402 Pubmed 2012 Constitutive neutrophil apoptosis: regulation by cell concentration via S100 A8/9 and the MEK-ERK pathway Atallah, Mizhir Krispin, Alon Trahtemberg, Uriel Ben-Hamron, Sandrine Grau, Amir Verbovetski, Inna Mevorach, Dror PLoS ONE 7:e29333 19451397 Pubmed 2009 The endogenous Toll-like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer Ehrchen, Jan M Sunderkötter, Cord Foell, Dirk Vogl, Thomas Roth, Johannes J. Leukoc. Biol. 86:557-66 16216873 Pubmed 2005 S100A8 and S100A9 in human arterial wall. Implications for atherogenesis McCormick, Michelle M Rahimi, Farid Bobryshev, Yuri V Gaus, Katharina Zreiqat, Hala Cai, Hong Lord, Reginald S A Geczy, Carolyn L J. Biol. Chem. 280:41521-9 22489132 Pubmed 2012 Pro-Inflammatory S100A8 and S100A9 Proteins: Self-Assembly into Multifunctional Native and Amyloid Complexes Vogl, Thomas Gharibyan, Anna L Morozova-Roche, Ludmilla A Int J Mol Sci 13:2893-917 26165843 Pubmed 2015 Eritoran inhibits S100A8-mediated TLR4/MD-2 activation and tumor growth by changing the immune microenvironment Deguchi, A Tomita, T Ohto, U Takemura, K Kitao, A Akashi-Takamura, S Miyake, K Maru, Y Oncogene 21782178 Pubmed 2011 Myeloid related proteins activate Toll-like receptor 4 in human acute coronary syndromes Yonekawa, Keiko Neidhart, Michel Altwegg, Lukas A Wyss, Christophe A Corti, Roberto Vogl, Thomas Grigorian, Mariam Gay, Steffen Lüscher, Thomas F Maier, Willibald Atherosclerosis 218:486-92 22127564 Pubmed 2012 Alarmins S100A8 and S100A9 elicit a catabolic effect in human osteoarthritic chondrocytes that is dependent on Toll-like receptor 4 Schelbergen, Rik F P Blom, Arjen B van den Bosch, Martijn H J Slöetjes, Annet Abdollahi-Roodsaz, Shahla Schreurs, B Wim Mort, John S Vogl, Thomas Roth, Johannes van den Berg, Wim B van Lent, Peter L E M Arthritis Rheum. 64:1477-87 16943388 Pubmed 2007 S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules Foell, Dirk Wittkowski, Helmut Vogl, Thomas Roth, Johannes J. Leukoc. Biol. 81:28-37 16682612 Pubmed 2006 Platelet expression profiling and clinical validation of myeloid-related protein-14 as a novel determinant of cardiovascular events Healy, Aileen M Pickard, Michael D Pradhan, Aruna D Wang, Yunmei Chen, Zhiping Croce, Kevin Sakuma, Masashi Shi, Can Zago, Alexandre C Garasic, Joseph Damokosh, Andrew I Dowie, Tracy L Poisson, Louis Lillie, James Libby, Peter Ridker, Paul M Simon, Daniel I Circulation 113:2278-84 24202303 Pubmed 2014 Plasma S100A8/A9 correlates with blood neutrophil counts, traditional risk factors, and cardiovascular disease in middle-aged healthy individuals Cotoi, Ovidiu S Dunér, Pontus Ko, Nayoung Hedblad, Bo Nilsson, Jan Björkbacka, Harry Schiopu, Alexandru Arterioscler. Thromb. Vasc. Biol. 34:202-10 26249667 Pubmed 2015 MRP8/14 serum levels as a predictor of response to starting and stopping anti-TNF treatment in juvenile idiopathic arthritis Anink, Janneke Van Suijlekom-Smit, Lisette W A Otten, Marieke H Prince, Femke H M van Rossum, Marion A J Dolman, Koert M Hoppenreijs, Esther P A H ten Cate, Rebecca Ursu, Simona Wedderburn, Lucy R Horneff, Gerd Frosch, Michael Vogl, Thomas Gohar, Faekah Foell, Dirk Roth, Johannes Holzinger, Dirk Arthritis Res. Ther. 17:200 23874727 Pubmed 2013 High levels of S100A8/A9 proteins aggravate ventilator-induced lung injury via TLR4 signaling Kuipers, Maria T Vogl, Thomas Aslami, Hamid Jongsma, Geartsje van den Berg, Elske Vlaar, Alexander P J Roelofs, Joris J T H Juffermans, Nicole P Schultz, Marcus J van der Poll, Tom Roth, Johannes Wieland, Catharina W PLoS ONE 8:e68694 24975020 Pubmed 2015 S100A8, S100A9 and S100A12 activate airway epithelial cells to produce MUC5AC via extracellular signal-regulated kinase and nuclear factor-κB pathways Kang, Jin Hyun Hwang, Sae Mi Chung, Il Yup Immunology 144:79-90 20473308 Pubmed 2010 The Toll-like receptor 4 ligands Mrp8 and Mrp14 are crucial in the development of autoreactive CD8+ T cells Loser, Karin Vogl, Thomas Voskort, Maik Lueken, Aloys Kupas, Verena Nacken, Wolfgang Klenner, Lars Kuhn, Annegret Foell, Dirk Sorokin, Lydia Luger, Thomas A Roth, Johannes Beissert, Stefan Nat. Med. 16:713-7 17767165 Pubmed 2007 Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock Vogl, Thomas Tenbrock, Klaus Ludwig, Stephan Leukert, Nadja Ehrhardt, Christina van Zoelen, Marieke A D Nacken, Wolfgang Foell, Dirk van der Poll, Tom Sorg, Clemens Roth, Johannes Nat. Med. 13:1042-9 8445331 Pubmed 1993 MRP-8 and MRP-14, two abundant Ca(2+)-binding proteins of neutrophils and monocytes Hessian, P A Edgeworth, J Hogg, N J. Leukoc. Biol. 53:197-204 23626736 Pubmed 2013 Human S100A9 protein is stabilized by inflammatory stimuli via the formation of proteolytically-resistant homodimers Riva, Matteo He, Zhifei Källberg, Eva Ivars, Fredrik Leanderson, Tomas PLoS ONE 8:e61832 LEFT-TO-RIGHT S100A1 binds TLR4:LY96 The human event of S100A1 is inferred from the mouse data. <p>S100A1 is a Ca(2+)-sensing protein of the EF-hand family. S100A1 is expressed predominantly in cardiomyocytes, where it regulates Ca(2+)-dependent signaling events (Wright NT et al. 2005; Cannon BR et al. 2011; Brinks H et al. 2011; Yu J et al. 2015; Rohde D et al. 2014; Ritterhoff J & Most P 2012). In response to ischemic/hypoxic damage of cardiomyocytes, S100A1 is released or transferred to the extracellular region through open channels on membrane (Rohde D et al. 2014). The extracellular S100A1 activates signal and promotes cell survival pathways, including inflammation response via Toll-like receptor 4 (TLR4) (Brinks H et al. 2011; Yu J et al. 2015; Rohde D et al. 2014). In rodent H9C2 cells S100A1 was found to regulate the inflammatory response and oxidative stress via TLR4/ROS/NFkappaB pathway ( Yu J et al. 2015). Authored: Shamovsky, Veronica, 2015-09-12 Reviewed: D'Eustachio, Peter, 2015-09-12 Reviewed: Granucci, Francesca, Zanoni, Ivan Edited: Shamovsky, Veronica, 2016-05-10 S100A1 dimer:Ca(2+) Reactome DB_ID: 6805958 S100A1 S-100 protein alpha chain Reactome DB_ID: 6805991 UniProt:P23297 S100A1 S100A1 S100A FUNCTION Small calcium binding protein that plays important roles in several biological processes such as Ca(2+) homeostasis, chondrocyte biology and cardiomyocyte regulation (PubMed:12804600). In response to an increase in intracellular Ca(2+) levels, binds calcium which triggers conformational changes (PubMed:23351007). These changes allow interactions with specific target proteins and modulate their activity (PubMed:22399290). Regulates a network in cardiomyocytes controlling sarcoplasmic reticulum Ca(2+) cycling and mitochondrial function through interaction with the ryanodine receptors RYR1 and RYR2, sarcoplasmic reticulum Ca(2+)-ATPase/ATP2A2 and mitochondrial F1-ATPase (PubMed:12804600). Facilitates diastolic Ca(2+) dissociation and myofilament mechanics in order to improve relaxation during diastole (PubMed:11717446).SUBUNIT Dimer of either two alpha chains, or two beta chains, or one alpha and one beta chain (PubMed:21296671). Also forms heterodimers with S100P (PubMed:15171681). Interacts with AGER (By similarity). Interacts with CAPZA1 (By similarity). Interacts with FKBP4 (PubMed:20188096). Interacts with RYR1 and RYR2 (PubMed:18650434). Interacts with CACYBP in a calcium-dependent manner (PubMed:12042313). Interacts with PPP5C (via TPR repeats); the interaction is calcium-dependent and modulates PPP5C activity (PubMed:22399290). Interacts with ATP2A2 and PLN in a Ca(2+)-dependent manner (PubMed:12804600). Interacts with mitochondrial F1-ATPase subunits ATP5F1A and ATP5F1B; these interactions increase F1-ATPase activity (By similarity).TISSUE SPECIFICITY Highly prevalent in heart (PubMed:12804600, PubMed:1384693). Also found in lesser quantities in skeletal muscle and brain (PubMed:1384693).PTM Glutathionylated; glutathionylation increases affinity to calcium about 10-fold.MISCELLANEOUS Able to bind zinc in vitro; the binding sites are different from the calcium binding sites. The physiological relevance of zinc binding is unclear. Physiological concentrations of potassium antagonize the binding of both divalent cations, especially affecting the high-affinity calcium-binding sites.SIMILARITY Belongs to the S-100 family. UniProt P23297 1 EQUAL 94 EQUAL Reactome Database ID Release 83 6805991 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6805991 Reactome R-HSA-6805991 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6805991.2 2 Ca2+ Calcium calcium(2+) Reactome DB_ID: 74112 calcium(2+) [ChEBI:29108] calcium(2+) ChEBI CHEBI:29108 Reactome Database ID Release 83 74112 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74112 Reactome R-ALL-74112 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-74112.4 COMPOUND C00076 4 Reactome Database ID Release 83 6805958 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6805958 Reactome R-HSA-6805958 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6805958.2 S100A1:TLR4:LY96 Reactome DB_ID: 6805997 1 1 Reactome Database ID Release 83 6805997 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6805997 Reactome R-HSA-6805997 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6805997.2 Reactome Database ID Release 83 6805943 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6805943 Reactome R-HSA-6805943 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6805943.2 26213580 Pubmed 2011 S100A1 (S100 calcium binding protein A1) Cannon, Brian R Zimmer, Danna B Weber, David J Atlas Genet Cytogenet Oncol Haematol 15:873-876 21851887 Pubmed 2011 S100A1 genetically targeted therapy reverses dysfunction of human failing cardiomyocytes Brinks, Henriette Rohde, David Voelkers, Mirko Qiu, Gang Pleger, Sven T Herzog, Nicole Rabinowitz, Joseph Ruhparwar, Arjang Silvestry, Scott Lerchenmüller, Carolin Mather, Paul J Eckhart, Andrea D Katus, Hugo A Carrel, Thierry Koch, Walter J Most, Patrick J. Am. Coll. Cardiol. 58:966-73 22336719 Pubmed 2012 Targeting S100A1 in heart failure Ritterhoff, J Most, P Gene Ther. 19:613-21 25880347 Pubmed 2015 Role of S100A1 in hypoxia-induced inflammatory response in cardiomyocytes via TLR4/ROS/NF-κB pathway Yu, Jiangkun Lu, Yanyu Li, Yapeng Xiao, Lili Xing, Yu Li, Yanshen Wu, Leiming J. Pharm. Pharmacol. 67:1240-50 16169012 Pubmed 2005 The three-dimensional solution structure of Ca(2+)-bound S100A1 as determined by NMR spectroscopy Wright, Nathan T Varney, Kristen M Ellis, Karen C Markowitz, Joseph Gitti, Rossitza K Zimmer, Danna B Weber, David J J. Mol. Biol. 353:410-26 25157660 Pubmed 2014 S100A1: a major player in cardiovascular performance Duarte-Costa, S Castro-Ferreira, R Neves, J S Leite-Moreira, A F Physiol Res 63:669-81 24833748 Pubmed 2014 S100A1 is released from ischemic cardiomyocytes and signals myocardial damage via Toll-like receptor 4 Rohde, David Schön, Christoph Boerries, Melanie Didrihsone, Ieva Ritterhoff, Julia Kubatzky, Katharina F Völkers, Mirko Herzog, Nicole Mähler, Mona Tsoporis, James N Parker, Thomas G Linke, Björn Giannitsis, Evangelos Gao, Erhe Peppel, Karsten Katus, Hugo A Most, Patrick EMBO Mol Med 6:778-94 LEFT-TO-RIGHT oxPL binds CD14 The generation of reactive oxygen species is a central feature of inflammation that results in the oxidation of host phospholipids. Endogenously formed oxidized phospholipids, such as 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (OxPAPC), have been shown to inhibit TLR4- & TLR2-mediated signaling induced by bacterial lipopeptide or lipopolysaccharide (LPS) in various human cells (Bochkov VN et al., 2002; von Schlieffen E et al., 2009). Oxidized phospholipids were found to bind LPS binding protein (LBP) and soluble CD14 suggesting that the binding prevented recognition of LPS by these proteins thus preventing recognition of LPS and activation of TLR4 (Erridge C et al., 2008; von Schlieffen E et al., 2009). In addition, oxPAPC protected mice treated with a lethal dose of LPS (Bochkov VN et al., 2002). Thus, oxidized phospholipids may function as a negative feedback to blunt innate immune responses. Authored: Shamovsky, Veronica, 2016-05-06 Reviewed: Granucci, Francesca, Zanoni, Ivan Edited: Shamovsky, Veronica, 2016-05-10 oxidised phospholipid oxidized phospholipids Reactome DB_ID: 2186967 oxidised phospholipid [ChEBI:60156] oxidised phospholipid oxidised phospholipids OxPL OxPLs oxidized phospholipids oxidized phospholipid ChEBI CHEBI:60156 Reactome Database ID Release 83 2186967 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2186967 Reactome R-ALL-2186967 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2186967.3 CD14(20-345) Secreted form of CD14 Reactome DB_ID: 166025 UniProt:P08571 CD14 CD14 FUNCTION Coreceptor for bacterial lipopolysaccharide (PubMed:1698311, PubMed:23264655). In concert with LBP, binds to monomeric lipopolysaccharide and delivers it to the LY96/TLR4 complex, thereby mediating the innate immune response to bacterial lipopolysaccharide (LPS) (PubMed:20133493, PubMed:23264655, PubMed:22265692). Acts via MyD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:8612135). Acts as a coreceptor for TLR2:TLR6 heterodimer in response to diacylated lipopeptides and for TLR2:TLR1 heterodimer in response to triacylated lipopeptides, these clusters trigger signaling from the cell surface and subsequently are targeted to the Golgi in a lipid-raft dependent pathway (PubMed:16880211). Binds electronegative LDL (LDL(-)) and mediates the cytokine release induced by LDL(-) (PubMed:23880187).SUBUNIT Interacts with LPS-bound LPB (PubMed:1698311, PubMed:23264655). Belongs to the lipopolysaccharide (LPS) receptor, a multi-protein complex containing at least CD14, LY96 and TLR4 (PubMed:11274165). Interacts with LPAR1 (By similarity). Interacts with the TLR2:TLR6 or TLR2:TLR1 heterodimers; upon interaction with ligands such as diacylated lipopeptides and triacylated lipopeptides, respectively (PubMed:16880211). Interacts with MYO18A (PubMed:25965346). Interacts with FSTL1 (PubMed:22265692).TISSUE SPECIFICITY Detected on macrophages (at protein level) (PubMed:1698311). Expressed strongly on the surface of monocytes and weakly on the surface of granulocytes; also expressed by most tissue macrophages.INDUCTION The expression in monocytes is highly induced by 27-hydroxycholesterol, priming monocytes/macrophages such that LPS-mediated inflammatory reaction is accelerated. Secretion of soluble CD14 is also enhanced.DOMAIN The C-terminal leucine-rich repeat (LRR) region is required for responses to smooth LPS.PTM N- and O- glycosylated. O-glycosylated with a core 1 or possibly core 8 glycan. UniProt P08571 20 EQUAL 345 EQUAL Reactome Database ID Release 83 166025 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=166025 Reactome R-HSA-166025 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-166025.1 CD14:oxPL Reactome DB_ID: 8869691 1 1 Reactome Database ID Release 83 8869691 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8869691 Reactome R-HSA-8869691 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8869691.2 Reactome Database ID Release 83 8869694 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8869694 Reactome R-HSA-8869694 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8869694.2 19112167 Pubmed 2009 Multi-hit inhibition of circulating and cell-associated components of the toll-like receptor 4 pathway by oxidized phospholipids von Schlieffen, Elena Oskolkova, Olga V Schabbauer, Gernot Gruber, Florian Bluml, Stephan Genest, Melinda Kadl, Alexandra Marsik, Claudia Knapp, Sylvia Chow, Jesse Leitinger, Norbert Binder, Bernd R Bochkov, Valery N Arterioscler. Thromb. Vasc. Biol. 29:356-62 12214235 Pubmed 2002 Protective role of phospholipid oxidation products in endotoxin-induced tissue damage Bochkov, Valery N Kadl, Alexandra Huber, Joakim Gruber, Florian Binder, Bernd R Leitinger, Norbert Nature 419:77-81 12775576 Pubmed 2003 Specific phospholipid oxidation products inhibit ligand activation of toll-like receptors 4 and 2 Walton, Kimberly A Cole, Amy L Yeh, Michael Subbanagounder, Ganesamoorthy Krutzik, Stephan R Modlin, Robert L Lucas, Robert M Nakai, Junko Smart, Eric J Vora, Deven K Berliner, Judith A Arterioscler. Thromb. Vasc. Biol. 23:1197-203 18559343 Pubmed 2008 Oxidized phospholipid inhibition of toll-like receptor (TLR) signaling is restricted to TLR2 and TLR4: roles for CD14, LPS-binding protein, and MD2 as targets for specificity of inhibition Erridge, Clett Kennedy, Simon Spickett, Corinne M Webb, David J J. Biol. Chem. 283:24748-59 LEFT-TO-RIGHT oxPL binds LBP Antibacterial defence involves activation of neutrophils that generate reactive oxygen species (ROS) capable of killing bacteria. The ROS production results in the oxidation of host phospholipids. Endogenously formed oxidized phospholipids, such as 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (OxPAPC), have been shown to inhibit TLR4- & TLR2-mediated signaling induced by bacterial lipopeptide or lipopolysaccharide (LPS) in various human cells (Bochkov VN et al., 2002; von Schlieffen E et al., 2009). Oxidized phospholipids were found to bind LPS binding protein (LBP) and soluble CD14 suggesting that the binding prevented recognition of LPS by these proteins thus preventing recognition of LPS and activation of TLR4 (Erridge C et al., 2008; von Schlieffen E et al., 2009). In addition, oxPAPC protected mice treated with a lethal dose of LPS (Bochkov VN et al., 2002). Thus, oxidized phospholipids may function as a negative feedback to blunt innate immune responses. Authored: Shamovsky, Veronica, 2016-05-06 Reviewed: Granucci, Francesca, Zanoni, Ivan Edited: Shamovsky, Veronica, 2016-05-10 LBP Reactome DB_ID: 166010 UniProt:P18428 LBP LBP FUNCTION Plays a role in the innate immune response. Binds to the lipid A moiety of bacterial lipopolysaccharides (LPS), a glycolipid present in the outer membrane of all Gram-negative bacteria (PubMed:7517398, PubMed:24120359). Acts as an affinity enhancer for CD14, facilitating its association with LPS. Promotes the release of cytokines in response to bacterial lipopolysaccharide (PubMed:7517398, PubMed:24120359).SUBUNIT When bound to LPS, interacts (via C-terminus) with soluble and membrane-bound CD14.TISSUE SPECIFICITY Detected in blood serum (at protein level).SIMILARITY Belongs to the BPI/LBP/Plunc superfamily. BPI/LBP family. UniProt P18428 26 EQUAL 481 EQUAL Reactome Database ID Release 83 166010 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=166010 Reactome R-HSA-166010 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-166010.1 LBP:oxPL Reactome DB_ID: 8869676 1 1 Reactome Database ID Release 83 8869676 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8869676 Reactome R-HSA-8869676 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8869676.2 Reactome Database ID Release 83 8869683 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8869683 Reactome R-HSA-8869683 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8869683.2 LEFT-TO-RIGHT oxLDL:CD36 binds TLR4:TLR6 Oxidized low-density lipoprotein (oxLDL) and amyloid-beta sequestered by the scavenger receptor CD36 trigger sterile inflammatory signaling through a CD36:TLR4:TLR6 heteromerization (Stewart CR et al., 2010). The heterotrimeric CD36:TLR4:TLR6 signaling complex, acting via NFkappaB and reactive oxygen species, primes the NLRP3 inflammasome in response to oxLDL (Sheedy FJ et al., 2013). Authored: Shamovsky, Veronica, 2016-05-06 Reviewed: Granucci, Francesca, Zanoni, Ivan Edited: Shamovsky, Veronica, 2016-05-10 TLR4:TLR6 Reactome DB_ID: 8869699 1 TLR6 Toll Like Receptor 6 Reactome DB_ID: 168061 UniProt:Q9Y2C9 TLR6 TLR6 FUNCTION Participates in the innate immune response to Gram-positive bacteria and fungi. Specifically recognizes diacylated and, to a lesser extent, triacylated lipopeptides (PubMed:20037584). In response to diacylated lipopeptides, forms the activation cluster TLR2:TLR6:CD14:CD36, this cluster triggers signaling from the cell surface and subsequently is targeted to the Golgi in a lipid-raft dependent pathway (PubMed:16880211). Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Recognizes mycoplasmal macrophage-activating lipopeptide-2kD (MALP-2), soluble tuberculosis factor (STF), phenol-soluble modulin (PSM) and B.burgdorferi outer surface protein A lipoprotein (OspA-L) cooperatively with TLR2 (PubMed:11441107). In complex with TLR4, promotes sterile inflammation in monocytes/macrophages in response to oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42. In this context, the initial signal is provided by oxLDL- or amyloid-beta 42-binding to CD36. This event induces the formation of a heterodimer of TLR4 and TLR6, which is rapidly internalized and triggers inflammatory response, leading to the NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion (PubMed:11441107, PubMed:20037584).SUBUNIT Homodimer (via cytoplasmic TIR domain) (PubMed:25088687). Heterodimer with TLR2 via their respective extracellular domains (PubMed:16880211). Binds MYD88 via their respective TIR domains (Probable). Interacts with CD36, following CD36 stimulation by oxLDL or amyloid-beta 42, and forms a heterodimer with TLR4. The trimeric complex is internalized and triggers inflammatory response. LYN kinase activity facilitates TLR4:TLR6 heterodimerization and signal initiation (PubMed:20037584). The heterodimer TLR2:TLR6 interacts with CD14 and CD36 in response to triacylated lipopeptides (PubMed:16880211).TISSUE SPECIFICITY Detected in monocytes, CD11c+ immature dendritic cells, plasmacytoid pre-dendritic cells and dermal microvessel endothelial cells.SIMILARITY Belongs to the Toll-like receptor family.CAUTION In some plant proteins and in human SARM1, the TIR domain has NAD(+) hydrolase (NADase) activity (By similarity). However, despite the presence of the catalytic Asp residue, the isolated TIR domain of human TLR4 lacks NADase activity (By similarity). Based on this, it is unlikely that Toll-like receptors have NADase activity. UniProt Q9Y2C9 32 EQUAL 796 EQUAL Reactome Database ID Release 83 168061 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168061 Reactome R-HSA-168061 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-168061.1 1 Reactome Database ID Release 83 8869699 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8869699 Reactome R-HSA-8869699 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8869699.2 ComplexPortal CPX-945 oxLDL:CD36 Reactome DB_ID: 8869680 GPIV 4xPalmC-CD36 Platelet glycoprotein IV GPIIIB CD36 antigen PAS IV PAS-4 protein Reactome DB_ID: 51645 UniProt:P16671 CD36 CD36 GP3B GP4 FUNCTION Multifunctional glycoprotein that acts as receptor for a broad range of ligands. Ligands can be of proteinaceous nature like thrombospondin, fibronectin, collagen or amyloid-beta as well as of lipidic nature such as oxidized low-density lipoprotein (oxLDL), anionic phospholipids, long-chain fatty acids and bacterial diacylated lipopeptides. They are generally multivalent and can therefore engage multiple receptors simultaneously, the resulting formation of CD36 clusters initiates signal transduction and internalization of receptor-ligand complexes. The dependency on coreceptor signaling is strongly ligand specific. Cellular responses to these ligands are involved in angiogenesis, inflammatory response, fatty acid metabolism, taste and dietary fat processing in the intestine (Probable). Binds long-chain fatty acids and facilitates their transport into cells, thus participating in muscle lipid utilization, adipose energy storage, and gut fat absorption (By similarity) (PubMed:18353783, PubMed:21610069). Mechanistically, binding of fatty acids activates downstream kinase LYN, which phosphorylates the palmitoyltransferase ZDHHC5 and inactivates it resulting in the subsequent depalmitoylation of CD36 and caveolar endocytosis (PubMed:32958780). In the small intestine, plays a role in proximal absorption of dietary fatty acid and cholesterol for optimal chylomicron formation, possibly through the activation of MAPK1/3 (ERK1/2) signaling pathway (By similarity) (PubMed:18753675). Involved in oral fat perception and preferences (PubMed:22240721, PubMed:25822988). Detection into the tongue of long-chain fatty acids leads to a rapid and sustained rise in flux and protein content of pancreatobiliary secretions (By similarity). In taste receptor cells, mediates the induction of an increase in intracellular calcium levels by long-chain fatty acids, leading to the activation of the gustatory neurons in the nucleus of the solitary tract (By similarity). Important factor in both ventromedial hypothalamus neuronal sensing of long-chain fatty acid and the regulation of energy and glucose homeostasis (By similarity). Receptor for thrombospondins, THBS1 and THBS2, mediating their antiangiogenic effects (By similarity). As a coreceptor for TLR4:TLR6 heterodimer, promotes inflammation in monocytes/macrophages. Upon ligand binding, such as oxLDL or amyloid-beta 42, interacts with the heterodimer TLR4:TLR6, the complex is internalized and triggers inflammatory response, leading to NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion, through the priming and activation of the NLRP3 inflammasome (By similarity) (PubMed:20037584). Selective and nonredundant sensor of microbial diacylated lipopeptide that signal via TLR2:TLR6 heterodimer, this cluster triggers signaling from the cell surface, leading to the NF-kappa-B-dependent production of TNF, via MYD88 signaling pathway and subsequently is targeted to the Golgi in a lipid-raft dependent pathway (By similarity) (PubMed:16880211).FUNCTION (Microbial infection) Directly mediates cytoadherence of Plasmodium falciparum parasitized erythrocytes and the internalization of particles independently of TLR signaling.SUBUNIT Interacts with THBS1 and THBS2; the interactions mediate the THBS antiangiogenic activity (PubMed:1371676). Upon interaction with a ligand, such as oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42, rapidly forms a complex with TLR4 and TLR6; the complex is internalized and triggers an inflammatory signal. Through its C-terminus, interacts with PTK2, PXN and LYN, but not with SRC. LYN kinase activity is required for facilitating TLR4:TLR6 heterodimerization and signal initiation (PubMed:1371676, PubMed:20037584). Upon interaction with ligands such as diacylated lipopeptides, interacts with the TLR2:TLR6 heterodimer (PubMed:16880211). Interacts with CD9, CD81, FCER1G, ITGB2 and/or ITGB2; forming a membrane heteromeric complex required for the internalization of CD36 and its ligands (By similarity).SUBUNIT (Microbial infection) Binds to Plasmodium falciparum EMP1.PTM N-glycosylated and O-glycosylated with a ratio of 2:1.PTM Palmitoylated by ZDHHC5. Palmitoylation is required for proper localization at the plasma membrane.PTM Ubiquitinated at Lys-469 and Lys-472. Ubiquitination is induced by fatty acids such as oleic acid and leads to degradation by the proteasome (PubMed:21610069, PubMed:18353783). Ubiquitination and degradation are inhibited by insulin which blocks the effect of fatty acids (PubMed:18353783).POLYMORPHISM Genetic variations in CD36 are involved in susceptibility to malaria and influence the severity and outcome of malaria infection [MIM:611162].SIMILARITY Belongs to the CD36 family. UniProt P16671 3 EQUAL S-palmitoyl-L-cysteine MOD MOD:00115 464 EQUAL 466 EQUAL 7 EQUAL 2 EQUAL 472 EQUAL Reactome Database ID Release 83 51645 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=51645 Reactome R-HSA-51645 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-51645.1 1 oxidized LDL oxidized low-density lipoprotein complex Reactome DB_ID: 2173761 oxidized apoB-100 10xdHF-10xglutamyl semialdehyde (Pro)-6xL-tyrosine residue-3xOxoH-2xmodified L-lysine residue-N'-formyl-L-kynurenine-APOB(28-4563) 10xdHF-10xglutamyl semialdehyde (Pro)-6xL-tyrosine residue-3xOxoH-2xmodified L-lysine residue-N'-formyl-L-kynurenine-APOB oxidized apolipoprotein B-100 Reactome DB_ID: 2173702 UniProt:P04114 APOB APOB FUNCTION Apolipoprotein B is a major protein constituent of chylomicrons (apo B-48), LDL (apo B-100) and VLDL (apo B-100). Apo B-100 functions as a recognition signal for the cellular binding and internalization of LDL particles by the apoB/E receptor.SUBUNIT Interacts with PCSK9 (PubMed:22580899). Interacts with MTTP (PubMed:26224785, PubMed:27206948). Interacts with AUP1 (PubMed:28183703).INDUCTION Up-regulated in response to enterovirus 71 (EV71) infection (at protein level).PTM Palmitoylated; structural requirement for proper assembly of the hydrophobic core of the lipoprotein particle.POLYMORPHISM Genetic variations in APOB define the low density lipoprotein cholesterol level quantitative trait locus 4 (LDLCQ4) [MIM:615558].DISEASE Defects in APOB associated with defects in other genes (polygenic) can contribute to hypocholesterolemia. UniProt P04114 2665 EQUAL L-tyrosine residue MOD MOD:00028 2845 EQUAL 4019 EQUAL 4531 EQUAL 680 EQUAL 883 EQUAL 583 EQUAL N'-formyl-L-kynurenine MOD MOD:00464 2507 EQUAL Oxohistidine (from histidine) MOD MOD:00971 4529 EQUAL 596 EQUAL 1020 EQUAL dihydroxyphenylalanine (Phe) MOD MOD:00465 144 EQUAL 276 EQUAL 3295 EQUAL 3923 EQUAL 3926 EQUAL 4380 EQUAL 4380 EQUAL 4451 EQUAL 56 EQUAL 1007 EQUAL glutamyl semialdehyde (Pro) MOD MOD:00478 145 EQUAL 2620 EQUAL 2659 EQUAL 3262 EQUAL 3293 EQUAL 3310 EQUAL 3593 EQUAL 65 EQUAL 663 EQUAL 2195 EQUAL modified L-lysine residue MOD MOD:00912 2208 EQUAL 28 EQUAL 4563 EQUAL Reactome Database ID Release 83 2173702 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2173702 Reactome R-HSA-2173702 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2173702.1 1 CHOL cholesterol Reactome DB_ID: 171149 cholesterol [ChEBI:16113] cholesterol cholest-5-en-3beta-ol ChEBI CHEBI:16113 Reactome Database ID Release 83 171149 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=171149 Reactome R-ALL-171149 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-171149.3 670 PL phospholipids phospholipid Reactome DB_ID: 171066 phospholipid [ChEBI:16247] phospholipid ChEBI CHEBI:16247 Reactome Database ID Release 83 171066 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=171066 Reactome R-ALL-171066 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-171066.3 690 TAGs triacylglycerols triglyceride Reactome DB_ID: 171126 triglyceride [ChEBI:17855] triglyceride ChEBI CHEBI:17855 Reactome Database ID Release 83 171126 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=171126 Reactome R-ALL-171126 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-171126.3 170 lysoPC lysophosphatidylcholine Reactome DB_ID: 2173763 lysophosphatidylcholine [ChEBI:60479] lysophosphatidylcholine lysophosphatidylcholines ChEBI CHEBI:60479 Reactome Database ID Release 83 2173763 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2173763 Reactome R-ALL-2173763 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2173763.4 1 hydroxy fatty acid Reactome DB_ID: 2173775 hydroxy fatty acid [ChEBI:24654] hydroxy fatty acid hydroxy fatty acids ChEBI CHEBI:24654 Reactome Database ID Release 83 2173775 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2173775 Reactome R-ALL-2173775 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2173775.2 1 7-ketocholesterol Reactome DB_ID: 2173786 7-ketocholesterol [ChEBI:64294] 7-ketocholesterol 7-oxocholesterol ChEBI CHEBI:64294 Reactome Database ID Release 83 2173786 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2173786 Reactome R-ALL-2173786 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2173786.2 1 CHEST cholesterol ester cholesteryl ester cholesterol esters Reactome DB_ID: 171076 cholesteryl ester [ChEBI:17002] cholesteryl ester ChEBI CHEBI:17002 Reactome Database ID Release 83 171076 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=171076 Reactome R-ALL-171076 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-171076.3 1500 hydroperoxy fatty acid Reactome DB_ID: 2173764 hydroperoxy fatty acid [ChEBI:64009] hydroperoxy fatty acid hydroperoxy fatty acids ChEBI CHEBI:64009 Reactome Database ID Release 83 2173764 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2173764 Reactome R-ALL-2173764 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2173764.2 1 Reactome Database ID Release 83 2173761 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2173761 Reactome R-HSA-2173761 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2173761.1 1 Reactome Database ID Release 83 8869680 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8869680 Reactome R-HSA-8869680 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8869680.2 TLR4:TLR6:CD36:oxLDL Reactome DB_ID: 8869674 1 1 Reactome Database ID Release 83 8869674 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8869674 Reactome R-HSA-8869674 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8869674.2 Reactome Database ID Release 83 8869667 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8869667 Reactome R-HSA-8869667 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8869667.2 23812099 Pubmed 2013 CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation Sheedy, Frederick J Grebe, Alena Rayner, Katey J Kalantari, Parisa Ramkhelawon, Bhama Carpenter, Susan B Becker, Christine E Ediriweera, Hasini N Mullick, Adam E Golenbock, DT Stuart, Lynda M Latz, Eicke Fitzgerald, Katherine A Moore, Kathryn J Nat. Immunol. 14:812-20 7685021 Pubmed 1993 CD36 is a receptor for oxidized low density lipoprotein Endemann, G Stanton, LW Madden, KS Bryant, CM White, RT Protter, AA J Biol Chem 268:11811-6 20037584 Pubmed 2010 CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer Stewart, Cameron R Stuart, Lynda M Wilkinson, Kim van Gils, Janine M Deng, Jiusheng Halle, Annett Rayner, Katey J Boyer, Laurent Zhong, Ruiqin Frazier, William A Lacy-Hulbert, Adam El Khoury, Joseph Golenbock, DT Moore, Kathryn J Nat. Immunol. 11:155-61 LEFT-TO-RIGHT Cleaved fibrinogen products bind TLR4:LY96 Fibrinogen, in addition to its role in coagulation, is also an acute phase protein of inflammation which can induce a cytokine production acting as an endogenous ligand for toll-like receptor 4 (TLR4) expressed on cells including macrophages and airway epithelial cells (Millien VO et al., 2013; Kuhns DB et al., 2007; Smiley ST et al., 2001). In human macrophages fibrinogen stimulated interleukin IL6 expression and extracellular signal-related kinase (ERK) phosphorylation ((Hodgkinson CP et al., 2008). In human embryonic kidney 293 (HEK293)-CD14-MD2 cells expressing TLR4, fibrinogen induced robust phosphorylation of ERK1, p38alpha and JNK and activated transcription factors NFkappaB, Elk1 and AP1 (Hodgkinson CP et al., 2008). Moreover, proteinases, such as thrombin, can cleave fibrinogen. In mice, exposure to endogenous or exogenous proteinases lead to hyperactivation of an antifungal pathway and lead to allergic airway inflammation through activation of TLR4-dependent signaling pathway by fibrinogen cleaved products (Millien VO et al., 2013) Authored: Shamovsky, Veronica, 2016-05-10 Reviewed: Granucci, Francesca, Zanoni, Ivan Edited: Shamovsky, Veronica, 2016-05-10 Converted from EntitySet in Reactome FGA, FGB, FGG Fibrinogen cleavage products Reactome DB_ID: 8870680 FGA(20-35) fibrinopeptide A Reactome DB_ID: 140867 UniProt:P02671 FGA FGA FUNCTION Cleaved by the protease thrombin to yield monomers which, together with fibrinogen beta (FGB) and fibrinogen gamma (FGG), polymerize to form an insoluble fibrin matrix. Fibrin has a major function in hemostasis as one of the primary components of blood clots. In addition, functions during the early stages of wound repair to stabilize the lesion and guide cell migration during re-epithelialization. Was originally thought to be essential for platelet aggregation, based on in vitro studies using anticoagulated blood. However, subsequent studies have shown that it is not absolutely required for thrombus formation in vivo. Enhances expression of SELP in activated platelets via an ITGB3-dependent pathway. Maternal fibrinogen is essential for successful pregnancy. Fibrin deposition is also associated with infection, where it protects against IFNG-mediated hemorrhage. May also facilitate the immune response via both innate and T-cell mediated pathways.SUBUNIT Heterohexamer; disulfide linked. Contains 2 sets of 3 non-identical chains (alpha, beta and gamma). The 2 heterotrimers are in head to head conformation with the N-termini in a small central domain.SUBUNIT (Microbial infection) Interacts with Staphylococcus aureus protein Fib; this interaction inhibits fibrinogen-dependent platelet aggregation and protects the bacteria form phagocytosis.TISSUE SPECIFICITY Detected in blood plasma (at protein level).DOMAIN A long coiled coil structure formed by 3 polypeptide chains connects the central nodule to the C-terminal domains (distal nodules). The long C-terminal ends of the alpha chains fold back, contributing a fourth strand to the coiled coil structure.PTM The alpha chain is normally not N-glycosylated (PubMed:23151259), even though glycosylation at Asn-686 was observed when a fragment of the protein was expressed in insect cells (PubMed:9689040). It is well known that heterologous expression of isolated domains can lead to adventitious protein modifications. Besides, glycosylation at Asn-686 is supported by large-scale glycoproteomics studies (PubMed:16335952 and PubMed:19159218), but the evidence is still quite tenuous. Most likely, Asn-686 is not glycosylated in the healthy human body, or only with low efficiency.PTM O-glycosylated.PTM Forms F13A-mediated cross-links between a glutamine and the epsilon-amino group of a lysine residue, forming fibronectin-fibrinogen heteropolymers.PTM About one-third of the alpha chains in the molecules in blood were found to be phosphorylated.PTM Conversion of fibrinogen to fibrin is triggered by thrombin, which cleaves fibrinopeptides A and B from alpha and beta chains, and thus exposes the N-terminal polymerization sites responsible for the formation of the soft clot. The soft clot is converted into the hard clot by factor XIIIA which catalyzes the epsilon-(gamma-glutamyl)lysine cross-linking between gamma chains (stronger) and between alpha chains (weaker) of different monomers.PTM Phosphorylated by FAM20C in the extracellular medium. UniProt P02671 20 EQUAL 35 EQUAL Reactome Database ID Release 83 140867 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=140867 Reactome R-HSA-140867 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-140867.1 FGB(31-44) fibrinopeptide B Reactome DB_ID: 140876 UniProt:P02675 FGB FGB FUNCTION Cleaved by the protease thrombin to yield monomers which, together with fibrinogen alpha (FGA) and fibrinogen gamma (FGG), polymerize to form an insoluble fibrin matrix. Fibrin has a major function in hemostasis as one of the primary components of blood clots. In addition, functions during the early stages of wound repair to stabilize the lesion and guide cell migration during re-epithelialization. Was originally thought to be essential for platelet aggregation, based on in vitro studies using anticoagulated blood. However subsequent studies have shown that it is not absolutely required for thrombus formation in vivo. Enhances expression of SELP in activated platelets. Maternal fibrinogen is essential for successful pregnancy. Fibrin deposition is also associated with infection, where it protects against IFNG-mediated hemorrhage. May also facilitate the antibacterial immune response via both innate and T-cell mediated pathways.SUBUNIT Heterohexamer; disulfide linked. Contains 2 sets of 3 non-identical chains (alpha, beta and gamma). The 2 heterotrimers are in head to head conformation with the N-termini in a small central domain.TISSUE SPECIFICITY Detected in blood plasma (at protein level).DOMAIN A long coiled coil structure formed by 3 polypeptide chains connects the central nodule to the C-terminal domains (distal nodules). The long C-terminal ends of the alpha chains fold back, contributing a fourth strand to the coiled coil structure.PTM Conversion of fibrinogen to fibrin is triggered by thrombin, which cleaves fibrinopeptides A and B from alpha and beta chains, and thus exposes the N-terminal polymerization sites responsible for the formation of the soft clot. The soft clot is converted into the hard clot by factor XIIIA which catalyzes the epsilon-(gamma-glutamyl)lysine cross-linking between gamma chains (stronger) and between alpha chains (weaker) of different monomers. UniProt P02675 31 EQUAL 44 EQUAL Reactome Database ID Release 83 140876 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=140876 Reactome R-HSA-140876 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-140876.1 FGG Fibrinogen gamma chain Reactome DB_ID: 140585 UniProt:P02679 FGG FGG PRO2061 FUNCTION Together with fibrinogen alpha (FGA) and fibrinogen beta (FGB), polymerizes to form an insoluble fibrin matrix. Has a major function in hemostasis as one of the primary components of blood clots. In addition, functions during the early stages of wound repair to stabilize the lesion and guide cell migration during re-epithelialization. Was originally thought to be essential for platelet aggregation, based on in vitro studies using anticoagulated blood. However, subsequent studies have shown that it is not absolutely required for thrombus formation in vivo. Enhances expression of SELP in activated platelets via an ITGB3-dependent pathway. Maternal fibrinogen is essential for successful pregnancy. Fibrin deposition is also associated with infection, where it protects against IFNG-mediated hemorrhage. May also facilitate the antibacterial immune response via both innate and T-cell mediated pathways.SUBUNIT Heterohexamer; disulfide linked. Contains 2 sets of 3 non-identical chains (alpha, beta and gamma). The 2 heterotrimers are in head to head conformation with the N-termini in a small central domain.TISSUE SPECIFICITY Detected in blood plasma (at protein level).DOMAIN A long coiled coil structure formed by 3 polypeptide chains connects the central nodule to the C-terminal domains (distal nodules). The long C-terminal ends of the alpha chains fold back, contributing a fourth strand to the coiled coil structure.PTM Conversion of fibrinogen to fibrin is triggered by thrombin, which cleaves fibrinopeptides A and B from alpha and beta chains, and thus exposes the N-terminal polymerization sites responsible for the formation of the soft clot. The soft clot is converted into the hard clot by factor XIIIA which catalyzes the epsilon-(gamma-glutamyl)lysine cross-linking between gamma chains (stronger) and between alpha chains (weaker) of different monomers.PTM Sulfation of C-terminal tyrosines increases affinity for thrombin.MISCELLANEOUS The gamma-chain carries the main binding site for the platelet receptor. UniProt P02679 27 EQUAL 453 EQUAL Reactome Database ID Release 83 140585 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=140585 Reactome R-HSA-140585 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-140585.1 Reactome Database ID Release 83 8870680 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8870680 Reactome R-HSA-8870680 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8870680.2 TLR4:LY96:cleaved fibrinogen Reactome DB_ID: 8870679 1 1 Reactome Database ID Release 83 8870679 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8870679 Reactome R-HSA-8870679 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8870679.2 Reactome Database ID Release 83 8870678 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8870678 Reactome R-HSA-8870678 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8870678.3 23950537 Pubmed 2013 Cleavage of fibrinogen by proteinases elicits allergic responses through Toll-like receptor 4 Millien, Valentine Ongeri Lu, Wen Shaw, Joanne Yuan, Xiaoyi Mak, Garbo Roberts, Luz Song, Li-Zhen Knight, J Morgan Creighton, Chad J Luong, Amber Kheradmand, Farrah Corry, David B Science 341:792-6 17624583 Pubmed 2007 Induction of human monocyte interleukin (IL)-8 by fibrinogen through the toll-like receptor pathway Kuhns, Douglas B Priel, Debra A Long Gallin, John I Inflammation 30:178-88 11509636 Pubmed 2001 Fibrinogen stimulates macrophage chemokine secretion through toll-like receptor 4 Smiley, ST King, JA Hancock, WW J Immunol 167:2887-94 Reactome Database ID Release 83 5686938 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5686938 Reactome R-HSA-5686938 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5686938.3 25391648 Pubmed 2014 Complexity of danger: the diverse nature of damage-associated molecular patterns Schaefer, Liliana J. Biol. Chem. 289:35237-45 20706656 Pubmed 2010 DAMPening inflammation by modulating TLR signalling Piccinini, A M Midwood, K S Mediators Inflamm. 2010: 20179153 Pubmed 2010 Endogenous ligands of TLR2 and TLR4: agonists or assistants? Erridge, Clett J. Leukoc. Biol. 87:989-99 20629986 Pubmed 2010 Endogenous toll-like receptor ligands and their biological significance Yu, Li Wang, Liantang Chen, Shangwu J. Cell. Mol. Med. 14:2592-603 19540364 Pubmed 2010 Peptidylarginine deiminase 4 and citrullination in health and disease Anzilotti, Consuelo Pratesi, Federico Tommasi, Cristina Migliorini, Paola Autoimmun Rev 9:158-60 23028349 Pubmed 2012 Citrullination of histone H3 interferes with HP1-mediated transcriptional repression Sharma, Priyanka Azebi, Saliha England, Patrick Christensen, Tove Møller-Larsen, Anné Petersen, Thor Batsché, Eric Muchardt, Christian PLoS Genet. 8:e1002934 20954191 Pubmed 2011 Immune complexes containing citrullinated fibrinogen costimulate macrophages via Toll-like receptor 4 and Fcγ receptor Sokolove, Jeremy Zhao, Xiaoyan Chandra, Piyanka E Robinson, William H Arthritis Rheum. 63:53-62 23234648 Pubmed 2013 Citrullination enhances the pro-inflammatory response to fibrin in rheumatoid arthritis synovial fibroblasts Sanchez-Pernaute, Olga Filkova, Maria Gabucio, Antonio Klein, Martin Maciejewska-Rodrigues, Hanna Ospelt, Caroline Brentano, Fabia Michel, Beat A Gay, Renate E Herrero-Beaumont, Gabriel Gay, Steffen Neidhart, Michel Juengel, Astrid Ann. Rheum. Dis. 72:1400-6