Search results for STAT1

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Identifier: R-HSA-909733
Species: Homo sapiens
Type I interferons (IFNs) are composed of various genes including IFN alpha (IFNA), beta (IFNB), omega, epsilon, and kappa. In humans the IFNA genes are composed of more than 13 subfamily genes, whereas there is only one IFNB gene. The large family of IFNA/B proteins all bind to a single receptor which is composed of two distinct chains: IFNAR1 and IFNAR2. The IFNA/B stimulation of the IFNA receptor complex leads to the formation of two transcriptional activator complexes: IFNA-activated-factor (AAF), which is a homodimer of STAT1 and IFN-stimulated gene factor 3 (ISGF3), which comprises STAT1, STAT2 and a member of the IRF family, IRF9/P48. AAF mediates activation of the IRF-1 gene by binding to GAS (IFNG-activated site), whereas ISGF3 activates several IFN-inducible genes including IRF3 and IRF7.
Identifier: R-HSA-937039
Species: Homo sapiens
Compartment: cytosol, plasma membrane
The role of IRAK1 kinase activity in the activation of NF-kappa-B by IL-1/TLR is still uncertain. It has been shown that a kinase-dead IRAK1 mutants can still activate NF-kappa-B. Furthermore, stimulation of IRAK1-deficient I1A 293 cells with LMP1 (latent membrane protein 1- a known viral activator of NF-kappa-B) leads to TRAF6 polyubiquitination and IKKbeta activation [Song et al 2006]. On the other hand, IRAK1 enhances p65 Ser536 phosphorylation [Song et al 2006] and p65 binding to the promoter of NF-kappa-B dependent target genes [Liu G et al 2008].

IRAK1 has also been shown to be itself Lys63-polyubiquitinated (probably by Pellino proteins, which have E3 ligase activity). Mutation of the ubiquitination sites on IRAK1 prevented interaction with the NEMO subunit of IKK complex and subsequent IL-1/TLR-induced NF-kappa-B activation [Conze et al 2008]. These data suggest that kinase activity of IRAK1 is not essential for its ability to activate NF-kappa-B, while its Lys63-polyubuquitination allows IRAK1 to bind NEMO thus facilitating association of TRAF6 and TAK1 complex with IKK complex followed by induction of NF-kappa-B.

Upon IL-1/TLR stimulation IRAK1 protein can undergo covalent modifications including phosphorylation [Kollewe et al 2004], ubiquitination [Conze DB et al 2008] and sumoylation [Huang et al 2004]. Depending upon the nature of its modification, IRAK1 may perform distinct functions including activation of IRF5/7 [Uematsu et al 2005, Schoenemeyer et al 2005], NF-kappa-B [Song et al 2006], and Stat1/3 [Huang et al 2004, Nguyen et al 2003].

Identifier: R-HSA-975144
Species: Homo sapiens
Compartment: endosome membrane, cytosol
The role of IRAK1 kinase activity in the activation of NF-kappa-B by IL-1/TLR is still uncertain. It has been shown that a kinase-dead IRAK1 mutants can still activate NF-kappa-B. Furthermore, stimulation of IRAK1-deficient I1A 293 cells with LMP1 (latent membrane protein 1- a known viral activator of NF-kappa-B) leads to TRAF6 polyubiquitination and IKKbeta activation [Song et al 2006]. On the other hand, IRAK1 enhances p65 Ser536 phosphorylation [Song et al 2006] and p65 binding to the promoter of NF-kappa-B dependent target genes [Liu G et al 2008].

IRAK1 has also been shown to be itself Lys63-polyubiquitinated (probably by Pellino proteins, which have E3 ligase activity). Mutation of the ubiquitination sites on IRAK1 prevented interaction with the NEMO subunit of IKK complex and subsequent IL-1/TLR-induced NF-kappa-B activation [Conze et al 2008]. These data suggest that kinase activity of IRAK1 is not essential for its ability to activate NF-kappa-B, while its Lys63-polyubuquitination allows IRAK1 to bind NEMO thus facilitating association of TRAF6 and TAK1 complex with IKK complex followed by induction of NF-kappa-B.

Upon IL-1/TLR stimulation IRAK1 protein can undergo covalent modifications including phosphorylation [Kollewe et al 2004], ubiquitination [Conze DB et al 2008] and sumoylation [Huang et al 2004]. Depending upon the nature of its modification, IRAK1 may perform distinct functions including activation of IRF5/7 [Uematsu et al 2005, Schoenemeyer et al 2005], NF-kappa-B [Song et al 2006], and Stat1/3 [Huang et al 2004, Nguyen et al 2003].

Identifier: R-HSA-8939902
Species: Homo sapiens
Compartment: nucleoplasm
Several transcription factors have been implicated in regulation of the RUNX2 gene transcription. Similar to the RUNX1 gene, the RUNX2 gene expression can be regulated from the proximal P2 promoter or the distal P1 promoter (reviewed in Li and Xiao 2007).
Activated estrogen receptor alpha (ESR1) binds estrogen response elements (EREs) in the P2 promoter and stimulates RUNX2 transcription (Kammerer et al. 2013). Estrogen-related receptor alpha (ERRA) binds EREs or estrogen-related response elements (ERREs) in the P2 promoter of RUNX2. When ERRA is bound to its co-factor PPARG1CA (PGC1A), it stimulates RUNX2 transcription. When bound to its co-factor PPARG1CB (PGC1B), ERRA represses RUNX2 transcription (Kammerer et al. 2013).
TWIST1, a basic helix-loop-helix (bHLH) transcription factor, stimulates RUNX2 transcription by binding to the E1-box in the P2 promoter (Yang, Yang et al. 2011). TWIST proteins also interact with the DNA-binding domain of RUNX2 to modulate its activity during skeletogenesis (Bialek et al. 2004). Schnurri-3 (SHN3) is another protein that interacts with RUNX2 to decrease its availability in the nucleus and therefore its activity (Jones et al. 2006). In contrast, RUNX2 and SATB2 interact to enhance the expression of osteoblast-specific genes (Dobreva et al. 2006). Formation of the heterodimer with CBFB (CBF-beta) also enhances the transcriptional activity of RUNX2 (Kundu et al. 2002, Yoshida et al. 2002, Otto et al. 2002).
Transcription of RUNX2 from the proximal promoter is inhibited by binding of the glucocorticoid receptor (NR3C1) activated by dexamethasone (DEXA) to a glucocorticoid receptor response element (GRE), which is also present in the human promoter (Zhang et al. 2012).
NKX3-2 (BAPX1), required for embryonic development of the axial skeleton (Tribioli and Lufkin 1999), binds the distal (P1) promoter of the RUNX2 gene and inhibits its transcription (Lengner et al. 2005). RUNX2-P1 transcription is also autoinhibited by RUNX2-P1, which binds to RUNX2 response elements in the P1 promoter of RUNX2 (Drissi et al. 2000). In contrast, binding of RUNX2-P2 to the proximal P2 promoter autoactivates transcription of RUNX2-P2 (Ducy et al. 1999). Binding of a homeodomain transcription factor DLX5, and possibly DLX6, to the RUNX2 P1 promoter stimulates RUNX2 transcription (Robledo et al. 2002, Lee et al. 2005). The homeobox transcription factor MSX2 can bind to DLX5 sites in the promoter of RUNX2 and inhibit transcription of RUNX2-P1 (Lee et al. 2005).
Translocation of RUNX2 protein to the nucleus is inhibited by binding to non-activated STAT1 (Kim et al. 2003).
Several E3 ubiquitin ligases were shown to polyubiquitinate RUNX2, targeting it for proteasome-mediated degradation: STUB1 (CHIP) (Li et al. 2008), SMURF1 (Zhao et al. 2003, Yang et al. 2014), WWP1 (Jones et al. 2006), and SKP2 (Thacker et al. 2016).
Identifier: R-HSA-9020958
Species: Homo sapiens
Interleukin-21 (IL21) is a pleiotropic cytokine with four alpha-helical bundles. It is produced primarily by natural killer T cells, T follicular helper cells and TH17 cells, with lower levels of production by numerous other populations of lymphohaematopoietic cells (Spolski & Leonard 2014). IL21 binds Interleukin-21 receptor (IL21R, NILR) and Cytokine receptor common subunit gamma (IL2RG, GammaC).
IL21R has significant homology with the class I cytokine receptors Interleukin-2 receptor subunit beta (IL2RB) and Interleukin-4 receptor subunit alpha (IL4R) and was predicted to similarly form a complex with IL2RG. IL21R dimers can weakly bind and signal in response to IL21 but IL21 generates a much stronger response when IL21R is combined with IL2RG, which is required for a fully signaling capable IL21 receptor complex (Ozaki et al. 2000, Asao et al. 2001, Habib et al. 2002). IL21R can bind Janus kinase 1 (JAK1) (Ozaki et al. 2000) but IL2RG is required for IL21 induced signaling (Asao et al. 2001). The heteromeric IL21 receptor complex can activate JAK1, JAK3, Signal transducer and activator of transcription 1 (STAT1), STAT3, STAT4 and STAT5, depending on the cell type. In cultured T-cells IL21 induced phosphorylation of JAK1, JAK3, STAT1, STAT3 and weakly STAT5 (Asao et al. 2001). In primary CD4+ T cells IL21 induced the phosphorylation of STAT1 and STAT3 but not STAT5, whereas IL2 induced the phosphorylation of STAT5 and STAT1 but not STA3 (Bennet et al. 2003). IL21 stimulation of primary splenic B cells and the pro-B-cell line Ba-F3 induced the activation of JAK1, JAK3 and STAT5 (Habib et al. 2002). In primary human NK cells or the NK cell line NK-92, IL21 induced the activation of STAT1, STAT3, and STAT4 but not STAT5 (Strengell et al. 2002, 2003). IL21 activated STAT1 and STAT3 in human monocyte-derived macrophages (Vallières & Girard 2017).
Identifier: R-HSA-913531
Species: Homo sapiens
Interferons (IFNs) are cytokines that play a central role in initiating immune responses, especially antiviral and antitumor effects. There are three types of IFNs:Type I (IFN-alpha, -beta and others, such as omega, epsilon, and kappa), Type II (IFN-gamma) and Type III (IFN-lamda). In this module we are mainly focusing on type I IFNs alpha and beta and type II IFN-gamma. Both type I and type II IFNs exert their actions through cognate receptor complexes, IFNAR and IFNGR respectively, present on cell surface membranes. Type I IFNs are broadly expressed heterodimeric receptors composed of the IFNAR1 and IFNAR2 subunits, while the type II IFN receptor consists of IFNGR1 and IFNGR2. Type III interferon lambda has three members: lamda1 (IL-29), lambda2 (IL-28A), and lambda3 (IL-28B) respectively. IFN-lambda signaling is initiated through unique heterodimeric receptor composed of IFN-LR1/IF-28Ralpha and IL10R2 chains.
Type I IFNs typically recruit JAK1 and TYK2 proteins to transduce their signals to STAT1 and 2; in combination with IRF9 (IFN-regulatory factor 9), these proteins form the heterotrimeric complex ISGF3. In nucleus ISGF3 binds to IFN-stimulated response elements (ISRE) to promote gene induction.
Type II IFNs in turn rely upon the activation of JAKs 1 and 2 and STAT1. Once activated, STAT1 dimerizes to form the transcriptional regulator GAF (IFNG activated factor) and this binds to the IFNG activated sequence (GAS) elements and initiate the transcription of IFNG-responsive genes.
Like type I IFNs, IFN-lambda recruits TYK2 and JAK1 kinases and then promote the phosphorylation of STAT1/2, and induce the ISRE3 complex formation.
Identifier: R-HSA-8985947
Species: Homo sapiens
Interleukin 9 (IL9) binds interleukin 9 receptor a chain (IL9R) and the interleukin 2 receptor common gamma chain (IL2RG) to initiate IL9 signaling downstream cascade. IL9R colocalize with Interleukin 2 receptor α chain and MHC molecules in lipid rafts of human T lymphoma cells (Nizsalóczki et al. 2014). IL2RG is essential for IL9 dependent growth signal transduction (Kimura et al. 1995). IL9R (glycoprotein of 64 kDa) has saturable and specific binding sites with a Kd of 100 pM (Renauld et al. 1992). The activated IL9R complex recruits tyrosine kinase proteins from the Janus kinase (JAK) family: JAK1 (JAK1) and JAK3 (JAK3) for subsequent activation of the Signal transducer and activator of transcription (STAT) factors STAT1, STAT3 and STAT5. The activated STATs form STAT5 dimers and STAT1:STAT3 heterodimers (Neurath & Finotto 2016, Li & Rostami 2010).
Identifier: R-HSA-451927
Species: Homo sapiens
Compartment: plasma membrane
The interleukin-2 family (also called the common gamma chain cytokine family) consists of interleukin (IL)2, IL9, IL15 and IL21. Although sometimes considered to be within this family, the IL4 and IL7 receptors can form complexes with other receptor chains and are represented separately in Reactome. Receptors of this family associate with JAK1 and JAK3, primarily activating STAT5, although certain family members can also activate STAT1, STAT3 or STAT6.
Identifier: R-HSA-450282
Species: Homo sapiens
MAPKs are protein kinases that, once activated, phosphorylate their specific cytosolic or nuclear substrates at serine and/or threonine residues. Such phosphorylation events can either positively or negatively regulate substrate, and thus entire signaling cascade activity.

The major cytosolic target of activated ERKs are RSKs (90 kDa Ribosomal protein S6 Kinase). Active RSKs translocates to the nucleus and phosphorylates such factors as c-Fos(on Ser362), SRF (Serum Response Factor) at Ser103, and CREB (Cyclic AMP Response Element-Binding protein) at Ser133. In the nucleus activated ERKs phosphorylate many other targets such as MSKs (Mitogen- and Stress-activated protein kinases), MNK (MAP interacting kinase) and Elk1 (on Serine383 and Serine389). ERK can directly phosphorylate CREB and also AP-1 components c-Jun and c-Fos. Another important target of ERK is NF-KappaB. Recent studies reveals that nuclear pore proteins are direct substrates for ERK (Kosako H et al, 2009). Other ERK nuclear targets include c-Myc, HSF1 (Heat-Shock Factor-1), STAT1/3 (Signal Transducer and Activator of Transcription-1/3), and many more transcription factors.

Activated p38 MAPK is able to phosphorylate a variety of substrates, including transcription factors STAT1, p53, ATF2 (Activating transcription factor 2), MEF2 (Myocyte enhancer factor-2), protein kinases MSK1, MNK, MAPKAPK2/3, death/survival molecules (Bcl2, caspases), and cell cycle control factors (cyclin D1).

JNK, once activated, phosphorylates a range of nuclear substrates, including transcription factors Jun, ATF, Elk1, p53, STAT1/3 and many other factors. JNK has also been shown to directly phosphorylate many nuclear hormone receptors. For example, peroxisome proliferator-activated receptor 1 (PPAR-1) and retinoic acid receptors RXR and RAR are substrates for JNK. Other JNK targets are heterogeneous nuclear ribonucleoprotein K (hnRNP-K) and the Pol I-specific transcription factor TIF-IA, which regulates ribosome synthesis. Other adaptor and scaffold proteins have also been characterized as nonnuclear substrates of JNK.

Identifier: R-HSA-9705462
Species: Homo sapiens
Signaling by CSF3 causes its own inactivation, thereby preventing overproliferation of neutrophils (reviewed in Beekman and Touw 2010, Palande et al. 2013). Activated CSF3R recruits and activates JAK2, which phosphorylates STAT1, STAT3, and STAT5. The phosphorylated STATs transit to the nucleus and enhance the expression of SOCS1 and SOCS3, inhibitors of CSF3R signaling (inferred from mouse homologs). SOCS3, the principle negative regulator, binds the phosphorylated C-terminal region of CSF3R (Hörtner et al. 2002, van de Geijn et al. 2004, and inferred from mouse homologs) and acts in two ways: direct inhibition of the phosphorylation activity of JAK2 (van de Geijn et al. 2004) and promotion of endocytosis (Ward et al. 1999, Aarts et al. 2004, Irandoust et al. 2007) and ubiquitination (Irandoust et al. 2007, Wölfler et al. 2009) of CSF3R.
Identifier: R-HSA-1169408
Species: Homo sapiens
Compartment: cytosol
Interferon-stimulated gene 15 (ISG15) is a member of the ubiquitin-like (Ubl) family. It is strongly induced upon exposure to type I Interferons (IFNs), viruses, bacterial LPS, and other stresses. Once released the mature ISG15 conjugates with an array of target proteins, a process termed ISGylation. ISGylation utilizes a mechanism similar to ubiquitination, requiring a three-step enzymatic cascade. UBE1L is the ISG15 E1 activating enzyme which specifically activates ISG15 at the expense of ATP. ISG15 is then transfered from E1 to the E2 conjugating enzyme UBCH8 and then to the target protein with the aid of an ISG15 E3 ligase, such as HERC5 and EFP. Hundreds of target proteins for ISGylation have been identified. Several proteins that are part of antiviral signaling pathways, such as RIG-I, MDA5, Mx1, PKR, filamin B, STAT1, IRF3 and JAK1, have been identified as targets for ISGylation. ISG15 also conjugates some viral proteins, inhibiting viral budding and release. ISGylation appears to act either by disrupting the activity of a target protein and/or by altering its localization within the cell.
Identifier: R-HSA-877300
Species: Homo sapiens
Interferon-gamma (IFN-gamma) belongs to the type II interferon family and is secreted by activated immune cells-primarily T and NK cells, but also B-cells and APC. INFG exerts its effect on cells by interacting with the specific IFN-gamma receptor (IFNGR). IFNGR consists of two chains, namely IFNGR1 (also known as the IFNGR alpha chain) and IFNGR2 (also known as the IFNGR beta chain). IFNGR1 is the ligand binding receptor and is required but not sufficient for signal transduction, whereas IFNGR2 do not bind IFNG independently but mainly plays a role in IFNG signaling and is generally the limiting factor in IFNG responsiveness. Both IFNGR chains lack intrinsic kinase/phosphatase activity and thus rely on other signaling proteins like Janus-activated kinase 1 (JAK1), JAK2 and Signal transducer and activator of transcription 1 (STAT-1) for signal transduction. IFNGR complex in its resting state is a preformed tetramer and upon IFNG association undergoes a conformational change. This conformational change induces the phosphorylation and activation of JAK1, JAK2, and STAT1 which in turn induces genes containing the gamma-interferon activation sequence (GAS) in the promoter.
Identifier: R-HSA-9674555
Species: Homo sapiens
CSF3 (GCSF) is a cytokine that regulates production of neutrophils and granulocytes (reviewed in Panopoulos and Watowich 2008). CSF3 circulates extracellularly as a dimer and binds to the monomeric receptor CSF3R (GCSFR) on neutrophil precursors and mature neutrophils (reviewed in Futosi et al. 2013). CSF3R possesses no catalytic activity of its own and is constitutively associated with the kinases LYN (Corey et al. 1994) and JAK1 (Nicholson et al. 1994). Upon binding the CSF3 dimer, CSF3R dimerizes, is phosphorylated, and activates JAK-STAT signaling, RAS-RAF-MEK-ERK signaling, and PI3K signaling (reviewed in Basu et al. 2002, Roberts et al. 2005, Kendricks and Bogoyevitch 2007, Touw and van de Geijn 2007).
After dimerization of CSF3R, JAK1 associated with CSF3R is required for phosphorylation of tyrosine residues in the cytosolic domain of CSF3R which recruit further kinases such as JAK2, SYK, HCK, and TYK2 (reviewed in Sampson et al. 2007). Phosphorylated JAK1 and JAK2 then appear to act redundantly to phosphorylate STAT proteins (STAT1, STAT3, STAT5) which dimerize and transit to the nucleus to activate gene expression.
CSF3 signaling also activates the RAS pathway, resulting in activation of ERK1 and ERK2 and cellular proliferation. Phosphorylated CSF3R recruits both GRB2, which can act as a scaffold for RAS guanyl exchange factors SOS and VAV, and PTPN11 (SHP2), which activates RAS by dephosphorylating tyrosine-32 of RAS (Bunda et al. 2015). Association of SOS or VAV with the phosphorylated CSF3R has not yet been shown. The pathway to activation of PI3K is uncertain but appears to proceed via GAB2 bound to CSF3R.
Mutations in CSF3R can occur during the course of Kostmann disease, a severe congenital neutropenia (reviewed in Zeidler and Welte 2002, Zeidler 2005, Ward 2007, Vandenberghe and Beel 2011). Somatic mutations in CSF3R, principally truncations of the C-terminal region, are involved in the pathogenesis of severe congenital neutropenia and are associated with progression to acute myeloid leukemia (Dong et al. 1995, reviewed in Ward 2007, Beekman and Touw 2010, Xing and Zhao 2016). Loss or mutation of the C-terminal region of CSF3R interferes with inhibition and turnover of the receptor. Mutation of Thr-618 to Ile-618 in CSF3R causes spontaneous dimerization and consequent autoactivation leading to CSF3-independent signaling and chronic neutrophilic leukemia (Maxson et al. 2013).
Identifier: R-HSA-447115
Species: Homo sapiens
Interleukin-12 (IL-12) is a heterodimer of interleukin-12 subunit alpha (IL12A, IL-12p35) and interleukin-12 subunit beta (IL12B, IL-12p40). It is a potent immunoregulatory cytokine involved in the generation of cell mediated immunity to intracellular pathogens. It is produced by antigen presenting cells, including dendritic cells, macrophages/monocytes, neutrophils and some B cells (D'Andrea et al. 1992, Kobayashi et al.1989, Heufler et al.1996). It enhances the cytotoxic activity of natural killer (NK) cells and cytotoxic T cells, stimulating proliferation of activated NK and T cells and induces production of interferon gamma (IFN gamma) by these cells (Stern et al. 1990). IL-12 also plays an important role in immunomodulation by promoting cell mediated immunity through induction of a class 1 T helper cell (Th1) immune response. IL-12 may contribute to immunopathological conditions such as rheumatoid arthritis (McIntyre et al. 1996). The receptor for IL-12 is a heterodimer of IL-12Rbeta1 (IL12RB1) and IL-12Rbeta2 (IL12RB2), both highly homologous to Interleukin-6 receptor subunit beta (IL6ST,gp130). Each has an extracellular ligand binding domain, a transmembrane domain and a cytosolic domain containing box 1 and box 2 sequences that mediate binding of Janus family tyrosine kinases (JAKs). IL-12 binding is believed to bring about the heterodimerization and generation of a high affinity receptor complex capable of signal transduction. In this model, receptor dimerization leads to juxtaposition of the cytosolic domains and subsequent tyrosine phosphorylation and activation of JAK2 and TYK2. These activated kinases, in turn, tyrosine phosphorylate and activate several members of the signal transducer and activator of transcription (STAT) family, mainly STAT4, while also STAT1, STAT3 and STAT5 have been reported to be activated (Bacon et al. 1995, Jacobson et al. 1995, Yu et al. 1996, Gollob et al.1995). The STATs translocate to the nucleus to activate transcription of several genes, including IFN gamma. The production of IFN gamma has a pleiotropic effect in the cell, stimulating production of molecules important to cell mediated immunity. In particular, IFN gamma stimulates production of more IL-12 and sets up a positive regulation loop between IL-12 signaling and IFN gamma (Chan et al. 1991). The importance of IL-12 for this loop is demonstrated by IL-12 and STAT4 knockout mice that are severely compromised in IFN-gamma production (Kaplan et al. 1996; Magram et al. 1996), as well as by patients with IL12B mutations that are severely compromised in IFN-gamma production (Altare et al.1998).
Identifier: R-HSA-9680350
Species: Homo sapiens
Colony stimulating factor-1 (CSF1, CSF-1, also called macrophage colony stimulating factor, M-CSF) is a disulfide-linked dimer that stimulates the proliferation and differentiation of mononuclear phagocytes and the survival, proliferation, motility, and anti-inflammatory activity of macrophages (reviewed in Mouchemore et al. 2012, Stanley and Chitu 2014, Ushach and Zlotnik 2016, Dwyer et al. 2017 and inferred from mouse homologs in Caescu et al. 2015). The unliganded CSF1 receptor, CSF1R (CSF-1R) is either clustered or undergoing rapid dimer-monomer transitions at the cell surface (Li and Stanley 1991). The CSF1 dimer initially binds the D2 and D3 extracellular domains of a monomer of CSF1R (Wang et al. 1993, Chihara et al. 2010, Ma et al. 2012, Felix et al. 2015, and inferred from mouse homologs). A second monomer of CSF1R then binds the CSF1:CSF1R complex and the resulting dimerization of CSF1R activates its kinase activity (Elegheert et al. 2011, Felix et al. 2015, and inferred from mouse homologs). CSF1R initially trans-autophosphorylates tyrosine-561 in the juxtamembrane domain, relieving negative autoinhibition of kinase activity, resulting in the trans-autophosphorylation of 7 more tyrosine residues in its cytoplasmic domain (Rohrschneider et al. 1997, Chihara et al. 2010, and inferred from mouse homologs in Xiong et al. 2011).
The PIK3R1 (p85alpha) regulatory subunit of phosphatidylinositol 3-kinase (PI3K) binds phosphotyrosine-723 of CSF1R, phosphorylated SRC binds phosphotyrosine-561 of CSF1R, phosphorylated CBL binds CSF1R associated with SHC, and GRB2:SOS binds CSF1R (Saleem et al. 1995, and inferred from mouse homologs). The resulting activation of the catalytic subunit of PI3K (PIK2CA,B,G) produces phosphatidylinositol 3,4,5-trisphosphate which recruits effectors containing pleckstrin homology domains (PH domains) such as PKB (also called Akt) to the plasma membrane. Pathways activated by PI3K appear to both enhance proliferation, survival, and migration of macrophages (reviewed in Dwyer et al. 2017) and, via induction of miR21, suppress the inflammatory response by targeting mRNAs encoding multiple proinflammatory molecules.
Phospholipase C gamma2 (PLCG2) binds phosphotyrosine-723 of CSF1R, hydrolyzes phosphatidylcholine to yield choline phosphate (phosphocholine) and diacylglycerol, and promotes survival and differentiation of macrophages via PKCdelta (PRKCD) (inferred from mouse homologs).
GRB2 bound to SOS1 (GRB2:SOS1) transiently interacts with phosphotyrosine-699 of CSF1R. SOS1 promotes the exchange of GDP for GTP by KRAS, activating the RAS-RAF-ERK1,2 pathway that causes proliferation of macrophage precursors (inferred from mouse homologs). CBL transiently associates with and ubiquitinates the CSF1R, then is deubiquitinated and returned to the cytoplasm (inferred from mouse homologs).
Phosphorylated CSF1R also recruits STAT1 and STAT3, which are then phosphorylated (inferred from mouse homologs). The role of phosphorylated STAT1,3 in signaling by CSF1R is incompletely characterized.
CSF1R is a target for therapeutics, such as imatinib (reviewed in Kumari et al. 2018).
Identifier: R-HSA-1170546
Species: Homo sapiens
Prolactin (PRL) is a hormone secreted mainly by the anterior pituitary gland. It was originally identified by its ability to stimulate the development of the mammary gland and lactation, but is now known to have numerous and varied functions (Bole-Feysot et al. 1998). Despite this, few pathologies have been associated with abnormalities in prolactin receptor (PRLR) signaling, though roles in various forms of cancer and certain autoimmune disorders have been suggested (Goffin et al. 2002). A vast body of literature suggests effects of PRL in immune cells (Matera 1996) but PRLR KO mice have unaltered immune system development and function (Bouchard et al. 1999). In addition to the pituitary, numerous other tissues produce PRL, including the decidua and myometrium, certain cells of the immune system, brain, skin and exocrine glands such as the mammary, sweat and lacrimal glands (Ben-Jonathan et al. 1996). Pituitary PRL secretion is negatively regulated by inhibitory factors originating from the hypothalamus, the most important of which is dopamine, acting through the D2 subclass of dopamine receptors present in lactotrophs (Freeman et al. 2000). PRL-binding sites or receptors have been identified in numerous cells and tissues of adult mammals. Various forms of PRLR, generated by alternative splicing, have been reported in several species including humans (Kelly et al. 1991, Clevenger et al. 2003).

PRLR is a member of the cytokine receptor superfamily. Like many other members of this family, the first step in receptor activation was generally believed to be ligand-induced dimerization whereby one molecule of PRL bound to two molecules of receptor (Elkins et al. 2000). Recent reports suggest that PRLR pre-assembles at the plasma membrane in the absence of ligand (Gadd & Clevenger 2006, Tallet et al. 2011), suggesting that ligand-induced activation involves conformational changes in preformed PRLR dimers (Broutin et al. 2010).

PRLR has no intrinsic kinase activity but associates (Lebrun et al. 1994, 1995) with Janus kinase 2 (JAK2) which is activated following receptor activation (Campbell et al. 1994, Rui et al. 1994, Carter-Su et al. 2000, Barua et al. 2009). JAK2-dependent activation of JAK1 has also been reported (Neilson et al. 2007). It is generally accepted that activation of JAK2 occurs by transphosphorylation upon ligand-induced receptor activation, based on JAK activation by chimeric receptors in which various extracellular domains of cytokine or tyrosine kinase receptors were fused to the IL-2 receptor beta chain (see Ihle et al. 1994). This activation step involves the tyrosine phosphorylation of JAK2, which in turn phosphorylates PRLR on specific intracellular tyrosine residues leading to STAT5 recruitment and signaling, considered to be the most important signaling cascade for PRLR. STAT1 and STAT3 activation have also been reported (DaSilva et al. 1996) as have many other signaling pathways; signaling through MAP kinases (Shc/SOS/Grb2/Ras/Raf/MAPK) has been reported as a consequence of PRL stimuilation in many different cellular systems (see Bole-Feysot et al. 1998) though it is not clear how this signal is propagated. Other cascades non exhaustively include Src kinases, Focal adhesion kinase, phospholipase C gamma, PI3 kinase/Akt and Nek3 (Clevenger et al. 2003, Miller et al. 2007). The protein tyrosine phosphatase SHP2 is recruited to the C terminal tyrosine of PRLR and may have a regulatory role (Ali & Ali 2000). PRLR phosphotyrosines can recruit insulin receptor substrates (IRS) and other adaptor proteins to the receptor complex (Bole-Feysot et al. 1998).

Female homozygous PRLR knockout mice are completely infertile and show a lack of mammary development (Ormandy et al. 1997). Hemizogotes are unable to lactate following their first pregnancy and depending on the genetic background, this phenotype can persist through subsequent pregnancies (Kelly et al. 2001).
Identifier: R-HSA-6785807
Species: Homo sapiens
Interleukin-4 (IL4) is a principal regulatory cytokine during the immune response, crucially important in allergy and asthma (Nelms et al. 1999). When resting T cells are antigen-activated and expand in response to Interleukin-2 (IL2), they can differentiate as Type 1 (Th1) or Type 2 (Th2) T helper cells. The outcome is influenced by IL4. Th2 cells secrete IL4, which both stimulates Th2 in an autocrine fashion and acts as a potent B cell growth factor to promote humoral immunity (Nelms et al. 1999).

Interleukin-13 (IL13) is an immunoregulatory cytokine secreted predominantly by activated Th2 cells. It is a key mediator in the pathogenesis of allergic inflammation. IL13 shares many functional properties with IL4, stemming from the fact that they share a common receptor subunit. IL13 receptors are expressed on human B cells, basophils, eosinophils, mast cells, endothelial cells, fibroblasts, monocytes, macrophages, respiratory epithelial cells, and smooth muscle cells, but unlike IL4, not T cells. Thus IL13 does not appear to be important in the initial differentiation of CD4 T cells into Th2 cells, rather it is important in the effector phase of allergic inflammation (Hershey et al. 2003). IL4 and IL13 induce “alternative activation” of macrophages, inducing an anti-inflammatory phenotype by signaling through IL4R alpha in a STAT6 dependent manner. This signaling plays an important role in the Th2 response, mediating anti-parasitic effects and aiding wound healing (Gordon & Martinez 2010, Loke et al. 2002) There are two types of IL4 receptor complex (Andrews et al. 2006). Type I IL4R (IL4R1) is predominantly expressed on the surface of hematopoietic cells and consists of IL4R and IL2RG, the common gamma chain. Type II IL4R (IL4R2) is predominantly expressed on the surface of nonhematopoietic cells, it consists of IL4R and IL13RA1 and is also the type II receptor for IL13. (Obiri et al. 1995, Aman et al. 1996, Hilton et al. 1996, Miloux et al. 1997, Zhang et al. 1997). The second receptor for IL13 consists of IL4R and Interleukin-13 receptor alpha 2 (IL13RA2), sometimes called Interleukin-13 binding protein (IL13BP). It has a high affinity receptor for IL13 (Kd = 250 pmol/L) but is not sufficient to render cells responsive to IL13, even in the presence of IL4R (Donaldson et al. 1998). It is reported to exist in soluble form (Zhang et al. 1997) and when overexpressed reduces JAK-STAT signaling (Kawakami et al. 2001). It's function may be to prevent IL13 signalling via the functional IL4R:IL13RA1 receptor. IL13RA2 is overexpressed and enhances cell invasion in some human cancers (Joshi & Puri 2012).

The first step in the formation of IL4R1 (IL4:IL4R:IL2RB) is the binding of IL4 with IL4R (Hoffman et al. 1995, Shen et al. 1996, Hage et al. 1999). This is also the first step in formation of IL4R2 (IL4:IL4R:IL13RA1). After the initial binding of IL4 and IL4R, IL2RB binds (LaPorte et al. 2008), to form IL4R1. Alternatively, IL13RA1 binds, forming IL4R2. In contrast, the type II IL13 complex (IL13R2) forms with IL13 first binding to IL13RA1 followed by recruitment of IL4R (Wang et al. 2009).

Crystal structures of the IL4:IL4R:IL2RG, IL4:IL4R:IL13RA1 and IL13:IL4R:IL13RA1 complexes have been determined (LaPorte et al. 2008). Consistent with these structures, in monocytes IL4R is tyrosine phosphorylated in response to both IL4 and IL13 (Roy et al. 2002, Gordon & Martinez 2010) while IL13RA1 phosphorylation is induced only by IL13 (Roy et al. 2002, LaPorte et al. 2008) and IL2RG phosphorylation is induced only by IL4 (Roy et al. 2002).

Both IL4 receptor complexes signal through Jak/STAT cascades. IL4R is constitutively-associated with JAK2 (Roy et al. 2002) and associates with JAK1 following binding of IL4 (Yin et al. 1994) or IL13 (Roy et al. 2002). IL2RG constitutively associates with JAK3 (Boussiotis et al. 1994, Russell et al. 1994). IL13RA1 constitutively associates with TYK2 (Umeshita-Suyama et al. 2000, Roy et al. 2002, LaPorte et al. 2008, Bhattacharjee et al. 2013).

IL4 binding to IL4R1 leads to phosphorylation of JAK1 (but not JAK2) and STAT6 activation (Takeda et al. 1994, Ratthe et al. 2007, Bhattacharjee et al. 2013).

IL13 binding increases activating tyrosine-99 phosphorylation of IL13RA1 but not that of IL2RG. IL4 binding to IL2RG leads to its tyrosine phosphorylation (Roy et al. 2002). IL13 binding to IL4R2 leads to TYK2 and JAK2 (but not JAK1) phosphorylation (Roy & Cathcart 1998, Roy et al. 2002).

Phosphorylated TYK2 binds and phosphorylates STAT6 and possibly STAT1 (Bhattacharjee et al. 2013).

A second mechanism of signal transduction activated by IL4 and IL13 leads to the insulin receptor substrate (IRS) family (Kelly-Welch et al. 2003). IL4R1 associates with insulin receptor substrate 2 and activates the PI3K/Akt and Ras/MEK/Erk pathways involved in cell proliferation, survival and translational control. IL4R2 does not associate with insulin receptor substrate 2 and consequently the PI3K/Akt and Ras/MEK/Erk pathways are not activated (Busch-Dienstfertig & González-Rodríguez 2013).
Identifier: R-HSA-9692916
Species: Homo sapiens
Coronaviruses (CoVs) are positive-sense RNA viruses that replicate in the interior of double membrane vesicles (DMV) in the cytoplasm of infected cells (Stertz S et al. 2007; Knoops K et al. 2008). The viral replication and transcription are facilitated by virus-encoded non-structural proteins (SARS-CoV-1 nsp1–nsp16) that assemble to form a DMV-bound replication-transcription complex (RTC). The replication strategy of CoVs can generate both single-stranded RNA (ssRNA) and double-stranded RNA (dsRNA) species, that may act as pathogen-associated molecular patterns (PAMPs) recognized by pattern recognition receptor (PRR) such as toll-like receptor 7 (TLR7) and TLR8, antiviral innate immune response receptor RIG-I (also known as DEAD box protein 58, DDX58) and interferon-induced helicase C domain-containing protein 1 (IFIH1, also known as MDA5) (Cervantes-Barragan L et al. 2007; Chen Y et al. 2009, 2011; Daffis S et al. 2010; Li Y et al. 2013). The activated PRRs trigger signaling pathways to produce type I and type III interferons IFNs and proinflammatory mediators that perform antiviral functions. This Reactome module describes the mechanisms underlying PRR-mediated sensing of the severe acute respiratory syndrome coronavirus type 1 (SARS-CoV-1) infection. First, endosomal recognition of viral ssRNA occurs by means of TLR7 and TLR8 which detect GU-rich ssRNA sequences. Specifically, GU-rich ssRNA oligonucleotides derived from SARS-CoV-1 stimulated mononuclear phagocytes to release considerable levels of pro‑inflammatory cytokines TNF‑a, IL‑6 and IL‑12 via TLR7 and TLR8 (Li Y et al. 2013). Second, SARS-CoV-1 dsRNA replication intermediates can be recognized by cytoplasmic receptors DDX58 and IFIH1 which bind to mitochondrial antiviral-signaling protein (MAVS, IPS-1) to induce the IFN-mediated antiviral response. In addition, the module shows an antiviral function of interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) that directly binds and sequesters viral single-stranded uncapped 5′-ppp RNA and cap-0 RNA (Daffis S et al. 2010). This module also describes several strategies developed by SARS-CoV-1 to evade or alter host immunity, including escaping innate immune sensors, inhibiting IFN production and signaling, and evading antiviral function of IFN stimulated gene (ISG) products. For example, viral dsRNA replication intermediates derived from SARS‑CoV‑1 were shown to associate with RTC bound to double membrane vesicles, which protected viral RNA from sensing by DDX58 or IFIH1 (Stertz S et al. 2007; Knoops K et al. 2008). Further, SARS-CoV-1 encodes nsp14 and nsp16 which possess guanine-N7-methyltransferase activity and 2’-O-methyl-transferase activity respectively (Chen Y et al. 2009, 2011). SARS-CoV-1 nsp14 generates 5' cap-0 viral RNA (m7GpppN, guanine N7-methylated) and nsp16 further methylates cap-0 viral RNA. These viral RNA modifications mimic the 5'-cap structure of host mRNAs allowing the virus to efficiently evade recognition by cytosolic DDX58 and IFIH1 (Chen Y et al. 2009, 2011; Daffis S et al. 2010). The nsp16-mediated ribose 2′-O-methylation of viral RNA also blocks the antiviral function of IFIT1 complexes (Menachery VD et al. 2014). Further, the uridylate‐specific endoribonuclease (EndoU) activity of viral nsp15 degrades viral RNA to hide it from innate immune sensors (Bhardwaj K et al. 2006; Ricagno S et al. 2006). Moreover, SARS-CoV-1 encodes several proteins that directly bind to host targets associated with SARS‑CoV‑1 infection and cytokine production (Frieman M et al. 2009; Hu Y et al. 2017; Kopecky-Bromberg SA et al. 2007; Lindner H et al. 2005; Siu KL et al. 2009). This Reactome module describes several such binding events and their consequences. For example, as a de-ubiquitinating enzyme, viral nsp3 binds to and removes polyubiquitin chains of signaling proteins such as TRAF3, TRAF6, STING, IkBA, and IRF3 thereby modulating the formation of signaling complexes and the activation of IRF3/7 and NFkappaB (Sun L et al. 2012; Chen X et al. 2014; Li SW et al. 2016). This inhibits IFN production downstream of TLR7/8, DDX58, IFIH1, MAVS and STING signaling pathways. Binding of SARS-CoV-1 nucleocapsid (N) protein to E3 ubiquitin ligase TRIM25 inhibits TRIM25-mediated DDX58 ubiquitination and DDX58-mediated signaling pathway (Hu Y et al. 2017). Next, SARS‑CoV‑1 membrane (M) protein targets IBK1/IKBKE and TRAF3 to prevent the formation of the TRAF3:TANK:TBK1/IKBKE complex and thereby inhibits TBK1/IKBKE‑dependent activation of IRF3/IRF7 transcription factors downstream of DDX58, IFIH1 and adaptor MAVS (Siu KL et al. 2009; 2014). The ion channel activities of open reading frame 3a (orf3a or 3a) and E contribute to activation of the NLRP3 inflammasome leading to highly inflammatory pyroptotic cell death (Nieto‑Torres JL et al. 2015; Chen IY et al. 2019; Yue Y et al. 2018). Viral 3a promoted the NLRP3-mediated formation of PYCARD (ASC) speck by interaction with both TRAF3 and PYCARD (ASC) (Siu KL et al. 2019). Binding of 3a to caspase-1 (CASP1) enhanced CASP1-mediated cleavage of interleukin 1 beta (IL‑1β) downstream of the NLRP3 inflammasome pathway (Yue Y et al. 2018). Like 3a, SARS-CoV-1 8b was found to bind to NLRP3 activating the NLRP3 inflammasome and triggering IL‑1β release (Shi CS et al. 2019). 8b was also shown to bind IRF3, inhibiting subsequent IRF3 dimerization (Wong et al. 2018). At the plasma membrane, binding of SARS-CoV-1 7a to host BST2 disrupts the antiviral tethering function of BST2 which restricts the release of diverse mammalian enveloped viruses (Taylor JK et al. 2015). SARS-CoV-1 9b (orf9b) inhibits the MAVS-mediated production of type I IFNs by targeting TOMM70 on the mitochondria (Jiang HW et al. 2020). SARS-CoV-1 6 (orf6) inhibits the IFN signaling pathway by tethering karyopherins KPNA2 and KPNB1 to the endoplasmic reticulum (ER)/Golgi intermediate compartment (ERGIC) and thus blocking the KPNA1:KPNB1-dependent nuclear import of STAT1 (Frieman M et al. 2007). Binding of SARS-CoV-1 nsp1 to peptidyl-prolyl isomerases (PPIases) and calcipressin-3 (RCAN3) significantly activates the cyclophilin A/NFAT pathway, ultimately enhancing the induction of the IL-2 promoter (Pfefferle et al, 2011; Law et al, 2007). At last, SARS‑CoV‑1 3b, after translocating to the nucleus, binds to transcription factor RUNX1 and increases its promoting activity (Varshney et al, 2012).
Identifier: R-HSA-9705671
Species: Homo sapiens
Coronaviruses (CoVs) are positive-sense RNA viruses that replicate in the interior of double membrane vesicles (DMV) in the cytoplasm of infected cells (Stertz S et al. 2007; Knoops K et al. 2008; V'kovski P et al. 2021). The viral replication and transcription are facilitated by virus-encoded non-structural proteins (SARS-CoV-2 nsp1–nsp16) that assemble to form a DMV-bound replication-transcription complex (RTC) (V'kovski P et al. 2021). The replication strategy of CoVs can generate both single-stranded RNA (ssRNA) and double-stranded RNA (dsRNA) species, that may act as pathogen-associated molecular patterns (PAMPs) recognized by pattern recognition receptor (PRR) such as toll-like receptor 7 (TLR7) and TLR8, antiviral innate immune response receptor RIG-I (also known as DEAD box protein 58, DDX58) and interferon-induced helicase C domain-containing protein 1 (IFIH1, also known as MDA5) (Salvi V et al. 2021; Campbell GR et al. 2021; Rebendenne A et al. 2021). The activated PRRs trigger signaling pathways to produce type I and type III interferons IFNs and proinflammatory mediators that perform antiviral functions. This Reactome module describes the mechanisms underlying PRR-mediated sensing of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection. First, endosomal recognition of viral ssRNA occurs by means of TLR7 and TLR8, which detect GU-rich ssRNA sequences (Salvi V et al. 2021; Campbell GR et al. 2021). Second, SARS-CoV-2 dsRNA replication intermediates can be recognized by cytoplasmic receptors DDX58 and IFIH1 which bind to mitochondrial antiviral-signaling protein (MAVS, IPS-1) to induce the IFN-mediated antiviral response (Rebendenne A et al. 2021; Yin X et al. 2021). In addition, SARS-CoV-2 E can be sensed by TLR2 (Zheng M et al. 2021). Further, cellular nucleic acid-binding protein (CNBP) and La-related protein 1 (LARP1) can directly bind SARS-CoV-2 gRNA to repress SARS-CoV-2 replication (Schmidt N et al. 2021). This module also describes several strategies developed by SARS-CoV-2 to evade or alter host immunity, including escaping innate immune sensors, inhibiting IFN production and signaling, and evading antiviral function of IFN stimulated gene (ISG) products. For example, SARS-CoV-2 encodes nsp14 and nsp16 which possess guanine-N7-methyltransferase activity and 2’-O-methyl-transferase activity respectively (Ogando NS et al. 2020; Krafcikova P et al. 2020; Viswanatha T et al. 2020; Lin S et al. 2021; Yan L et al. 2021). In human coronaviruses nsp14 generates 5' cap-0 viral RNA (m7GpppN, guanine N7-methylated) and nsp16 further methylates cap-0 viral RNA. These viral RNA modifications mimic the 5'-cap structure of host mRNAs allowing the virus to efficiently evade recognition by cytosolic DDX58 and IFIH1 (Chen Y et al. 2009, 2011; Daffis S et al. 2010, shown for CoVs such as SARS-CoV-1 and MERS-CoV). Structural studies and computational analysis suggest that properties and biological functions of SARS-CoV-2 nsp14 and nsp16 could be very similar to these of SARS-CoV-1 (Rosas-Lemus M et al. 2020; Lin S et al. 2020; Viswanathan T et al. 2020; Krafcikova P et al. 2020; Jiang Y et al. 2020; Wilamowski M et al. 2021). Further, the uridylate‐specific endoribonuclease (EndoU) activity of SARS-CoV-2 nsp15 degrades viral RNA to hide it from innate immune sensors (Frazier MN et al. 2021). Moreover, SARS-CoV-2 encodes several proteins that directly bind to host targets associated with SARS‑CoV‑2 infection and cytokine production (Shin D et al. 2020; Viswanathan T et al. 2020; Xia H et al. 2020; Matsuyama T et al. 2020; Yuen CK et al. 2020; reviewed by Park A & Iwasaki A 2020). This Reactome module describes several such binding events and their consequences. For example, as a deubiquitinating and deISGylating enzyme, viral nsp3 binds to and removes ISG15 from signaling proteins such as IRF3 and IFIH1 thereby modulating the formation of signaling complexes and the activation of IRF3/7 and NF-kappaB (Liu CQ et al. 2021). Binding of SARS-CoV-2 nsp6, nsp13 or membrane (M) protein to cytosolic TBK1 prevents IRF3/7 activation and inhibits IFN production downstream of DDX58, IFIH1, MAVS and STING signaling pathways (Xia H et al. 2020; Sui L et al. 2021). Next, M protein targets MAVS to prevent the formation of the MAVS signalosome complex and thereby inhibits downstream signaling pathways of DDX58 and IFIH1 (Fu YZ et al. 2021). Binding of SARS-CoV-2 nucleocapsid (N) protein to E3 ubiquitin ligase TRIM25 inhibits TRIM25-mediated DDX58 ubiquitination and the DDX58 signaling pathway (Gori SG et al. 2021). N interacts with NLRP3 to promote the assembly and activation of the NLRP3 inflammasome (Pan P et al. 2021). The interaction between viral N and MASP2 promotes MASP2-mediated cleavage of C4 (Ali YM et al. 2021) and C2 (Kang S et al. 2021) leading to the hyperactivation of the complement system. Besides, viral N promotes NF-kappaB activation by targeting signaling complexes of TAK1 and IKK (Wu Y et al. 2021). The ion channel activities of accessory protein ORF3a or 3a (open reading frame 3a) and SARS‑CoV‑2 envelope (E) protein contribute to activation of the NLRP3 inflammasome leading to highly inflammatory pyroptotic cell death (based on findings for SARS-CoV-1, Siu KL et al. 2019). SARS-CoV-2 nsp5 protease (3CLpro) cleaves TAB1, a component of the TAK1 complex, thus inhibiting NF-kappaB activation (Moustaqil M et al .2021). 3CLpro targets NLRP12 which modulates the expression of inflammatory cytokines through the regulation of the NFkappaB and MAPK pathways (Moustaqil M et al. 2021). SARS-CoV-2 6 (ORF6) interacts with importin KPNA2 and components of the nuclear pore complex, NUP98 and RAE1, to block nuclear translocation of IRF3, STAT1 and STAT2 (Xia H et al. 2020; Miorin L et al. 2020). SARS-CoV-2 9b (ORF9b) inhibits the MAVS-mediated production of type I IFNs by targeting TOMM70 on the mitochondria (Jiang HW et al. 2020). Binding of mitochondrial viral 9 to IKBKG prevents MAVS-dependent NF-kappaB activation (Wu J et al. 2021). Although the evasion mechanisms are mainly conserved between SARS-CoV-1 and SARS-CoV-2 (Gordon DE et al. 2020), studies identified SARS-CoV-2-specific modulations of host immune response that may contribute to pathophysiological determinants of COVID-19 (Gordon DE et al. 2020; Schiller HB et al. 2021). This Reactome module describes several virus-host interactions identified in cells during SARS-CoV-2, but not SARS-CoV-1, infection. For example, SARS-CoV-2 8 (ORF8) regulates the expression of class I MHC on the surface of the infected cells through an autophagy-dependent lysosomal degradation of class I MHC (Zhang Y et al. 2021). At the plasma membrane, binding of secreted viral 8 to IL17RA activates IL17 signaling pathway leading to an increased secretion of cytokines/chemokines thus contributing to cytokine storm during SARS-CoV-2 infection (Lin X et al. 2021). Furthermore, SARS-CoV-2-host interactome and proteomics studies identified various human proteins that are targeted by SARS-CoV-2 proteins (Gordon DE et al. 2020a, b; Bojkova D et al. 2020; Stukalov A et al. 2021; Li J et al. 2021; Messina F et al. 2021). This Reactome module does not cover all identified SARS-CoV-2–human interactions; the module describes those associations that were functionally validated.
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