BioPAX pathway converted from "Influenza Virus Induced Apoptosis" in the Reactome database.Influenza Virus Induced ApoptosisInfluenza Virus Induced ApoptosisInfluenza A virus induces apoptosis in a variety of ways including activation of host TGF-beta by expression of viral NA, M1 and M2 proteins, and by the binding of viral PB1-F2 to host mitochondrial adenine nucleotide translocator 3 (ANT3).Authored: Gillespie, ME, 2013-11-18Reviewed: Gale M, Jr, 2004-05-12 19:00:00Edited: Gillespie, ME, 2013-11-18NA activation of TGF-betaNA activation of TGF-betaInfluenza A virus induces apoptosis in a variety of ways including by activation of host TGF-beta by viral neuraminidase (NA).Authored: Gillespie, ME, 2013-11-18Reviewed: Gale M, Jr, 2004-05-12 19:00:00Reactome DB_ID: 67910371plasma membraneGO0005886Large latent complex of TGFB1 [plasma membrane]Large latent complex of TGFB1Large latent complex of TGF-beta 1Reactome DB_ID: 51467812UniProt:P01137 TGFB1TGFB1TGFB1TGFBFUNCTION Transforming growth factor beta-1 proprotein: Precursor of the Latency-associated peptide (LAP) and Transforming growth factor beta-1 (TGF-beta-1) chains, which constitute the regulatory and active subunit of TGF-beta-1, respectively.FUNCTION Transforming growth factor beta-1: Multifunctional protein that regulates the growth and differentiation of various cell types and is involved in various processes, such as normal development, immune function, microglia function and responses to neurodegeneration (By similarity). Activation into mature form follows different steps: following cleavage of the proprotein in the Golgi apparatus, Latency-associated peptide (LAP) and Transforming growth factor beta-1 (TGF-beta-1) chains remain non-covalently linked rendering TGF-beta-1 inactive during storage in extracellular matrix (PubMed:29109152). At the same time, LAP chain interacts with 'milieu molecules', such as LTBP1, LRRC32/GARP and LRRC33/NRROS that control activation of TGF-beta-1 and maintain it in a latent state during storage in extracellular milieus (PubMed:2022183, PubMed:8617200, PubMed:8939931, PubMed:19750484, PubMed:22278742, PubMed:19651619). TGF-beta-1 is released from LAP by integrins (ITGAV:ITGB6 or ITGAV:ITGB8): integrin-binding to LAP stabilizes an alternative conformation of the LAP bowtie tail and results in distortion of the LAP chain and subsequent release of the active TGF-beta-1 (PubMed:22278742, PubMed:28117447). Once activated following release of LAP, TGF-beta-1 acts by binding to TGF-beta receptors (TGFBR1 and TGFBR2), which transduce signal (PubMed:20207738). While expressed by many cells types, TGF-beta-1 only has a very localized range of action within cell environment thanks to fine regulation of its activation by Latency-associated peptide chain (LAP) and 'milieu molecules' (By similarity). Plays an important role in bone remodeling: acts as a potent stimulator of osteoblastic bone formation, causing chemotaxis, proliferation and differentiation in committed osteoblasts (By similarity). Can promote either T-helper 17 cells (Th17) or regulatory T-cells (Treg) lineage differentiation in a concentration-dependent manner (By similarity). At high concentrations, leads to FOXP3-mediated suppression of RORC and down-regulation of IL-17 expression, favoring Treg cell development (By similarity). At low concentrations in concert with IL-6 and IL-21, leads to expression of the IL-17 and IL-23 receptors, favoring differentiation to Th17 cells (By similarity). Stimulates sustained production of collagen through the activation of CREB3L1 by regulated intramembrane proteolysis (RIP) (PubMed:25310401). Mediates SMAD2/3 activation by inducing its phosphorylation and subsequent translocation to the nucleus (PubMed:25893292, PubMed:29483653, PubMed:30696809). Can induce epithelial-to-mesenchymal transition (EMT) and cell migration in various cell types (PubMed:25893292, PubMed:30696809).SUBUNIT Homodimer; disulfide-linked (PubMed:20207738, PubMed:25209176, PubMed:28117447, PubMed:29109152). Interacts with the serine proteases, HTRA1 and HTRA3: the interaction with either inhibits TGFB1-mediated signaling. The HTRA protease activity is required for this inhibition (By similarity). May interact with THSD4; this interaction may lead to sequestration by FBN1 microfibril assembly and attenuation of TGFB signaling (By similarity). Interacts with CD109, DPT and ASPN (PubMed:9895299, PubMed:16754747, PubMed:17827158). Latency-associated peptide: Homodimer; disulfide-linked (PubMed:28117447, PubMed:29109152). Latency-associated peptide: Interacts with Transforming growth factor beta-1 (TGF-beta-1) chain; interaction is non-covalent and maintains (TGF-beta-1) in a latent state; each Latency-associated peptide (LAP) monomer interacts with TGF-beta-1 in the other monomer (PubMed:29109152). Latency-associated peptide: Interacts with LTBP1; leading to regulate activation of TGF-beta-1 (PubMed:2022183, PubMed:8617200, PubMed:8939931). Latency-associated peptide: Interacts with LRRC32/GARP; leading to regulate activation of TGF-beta-1 on the surface of activated regulatory T-cells (Tregs) (PubMed:19750484, PubMed:22278742, PubMed:19651619). Interacts with LRRC33/NRROS; leading to regulate activation of TGF-beta-1 in macrophages and microglia (Probable). Latency-associated peptide: Interacts (via cell attachment site) with integrins ITGAV and ITGB6 (ITGAV:ITGB6), leading to release of the active TGF-beta-1 (PubMed:22278742, PubMed:28117447). Latency-associated peptide: Interacts with NREP; the interaction results in a decrease in TGFB1 autoinduction (By similarity). Latency-associated peptide: Interacts with HSP90AB1; inhibits latent TGFB1 activation (PubMed:20599762). Transforming growth factor beta-1: Homodimer; disulfide-linked (PubMed:20207738, PubMed:25209176, PubMed:28117447, PubMed:29109152). Transforming growth factor beta-1: Interacts with TGF-beta receptors (TGFBR1 and TGFBR2), leading to signal transduction (PubMed:20207738).TISSUE SPECIFICITY Highly expressed in bone (PubMed:11746498, PubMed:17827158). Abundantly expressed in articular cartilage and chondrocytes and is increased in osteoarthritis (OA) (PubMed:11746498, PubMed:17827158). Colocalizes with ASPN in chondrocytes within OA lesions of articular cartilage (PubMed:17827158).PTM Transforming growth factor beta-1 proprotein: The precursor proprotein is cleaved in the Golgi apparatus by FURIN to form Transforming growth factor beta-1 (TGF-beta-1) and Latency-associated peptide (LAP) chains, which remain non-covalently linked, rendering TGF-beta-1 inactive.POLYMORPHISM In post-menopausal Japanese women, the frequency of Leu-10 is higher in subjects with osteoporosis than in controls.MISCELLANEOUS TGF-beta-1 is inactivated by fresolimumab (also named GC1008), a monoclonal-neutralizing antibody.SIMILARITY Belongs to the TGF-beta family.Reactomehttp://www.reactome.orgHomo sapiensNCBI Taxonomy9606UniProtP01137Chain Coordinates279EQUAL390EQUALReactome Database ID Release 756791037Database 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=6791037ReactomeR-HSA-67910371Reactome 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-6791037.1Reactome DB_ID: 1708521extracellular regionGO0005576Dimeric TGFB1 [extracellular region]Dimeric TGFB1Dimeric TGF-beta 1Reactome DB_ID: 1708382279EQUAL390EQUALReactome Database ID Release 75170852Database 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=170852ReactomeR-HSA-1708521Reactome 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-170852.1PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 195915UniProt:P03468 NANANAFUNCTION Catalyzes the removal of terminal sialic acid residues from viral and cellular glycoconjugates. Cleaves off the terminal sialic acids on the glycosylated HA during virus budding to facilitate virus release. Additionally helps virus spread through the circulation by further removing sialic acids from the cell surface. These cleavages prevent self-aggregation and ensure the efficient spread of the progeny virus from cell to cell. Otherwise, infection would be limited to one round of replication. Described as a receptor-destroying enzyme because it cleaves a terminal sialic acid from the cellular receptors. May facilitate viral invasion of the upper airways by cleaving the sialic acid moieties on the mucin of the airway epithelial cells. Likely to plays a role in the budding process through its association with lipid rafts during intracellular transport. May additionally display a raft-association independent effect on budding. Plays a role in the determination of host range restriction on replication and virulence. Sialidase activity in late endosome/lysosome traffic seems to enhance virus replication.ACTIVITY REGULATION Inhibited by the neuraminidase inhibitors zanamivir (Relenza) and oseltamivir (Tamiflu). These drugs interfere with the release of progeny virus from infected cells and are effective against all influenza strains. Resistance to neuraminidase inhibitors is quite rare.SUBUNIT Homotetramer.DOMAIN Intact N-terminus is essential for virion morphogenesis. Possesses two apical sorting signals, one in the ectodomain, which is likely to be a glycan, and the other in the transmembrane domain. The transmembrane domain also plays a role in lipid raft association.PTM N-glycosylated.MISCELLANEOUS The influenza A genome consist of 8 RNA segments. Genetic variation of hemagglutinin and/or neuraminidase genes results in the emergence of new influenza strains. The mechanism of variation can be the result of point mutations or the result of genetic reassortment between segments of two different strains.SIMILARITY Belongs to the glycosyl hydrolase 34 family.Influenza A virusNCBI Taxonomy11320UniProtP03468GO0016504GO molecular functionReactome Database ID Release 75169166Database 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=169166Reactome Database ID Release 75168865Database 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=168865ReactomeR-HSA-1688655Reactome 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-168865.58970987Pubmed1996Influenza virus neuraminidase activates latent transforming growth factor betaSchultz-Cherry, SHinshaw, VSJ Virol 70:8624-925535343Pubmed2015Influenza viral neuraminidase primes bacterial coinfection through TGF-β-mediated expression of host cell receptorsLi, NingRen, AihuiWang, XiaoshuangFan, XinZhao, YongGao, George FCleary, PatrickWang, BeinanProc. Natl. Acad. Sci. U.S.A. 112:238-4310823850Pubmed2000Dose-dependent changes in influenza virus-infected dendritic cells result in increased allogeneic T-cell proliferation at low, but not high, doses of virusOh, SMcCaffery, JMEichelberger, MCJ Virol 74:5460-99934696Pubmed1999Role of neuraminidase in influenza virus-induced apoptosisMorris, SJPrice, GEBarnett, JMHiscox, SASmith, HSweet, CJ Gen Virol 80:137-46GO0046730GO biological processPB1-F2 binds to the mitochondrial adenine nucleotide translocator 3 ANT3, inducing apoptosisPB1-F2 binds to the mitochondrial adenine nucleotide translocator 3 ANT3, inducing apoptosisInfluenza A virus induces apoptosis in a variety of ways including binding of viral PB1-F2 to host mitochondrial adenine nucleotide translocator 3 (ANT3).Authored: Gillespie, ME, 2013-11-18Reviewed: Gale M, Jr, 2004-05-12 19:00:00Reactome DB_ID: 51467891mitochondrial intermembrane spaceGO0005758UniProt:P0C0U1 PB1PB1PB1FUNCTION Plays an important role in promoting lung pathology in both primary viral infection and secondary bacterial infection. Promotes alteration of mitochondrial morphology, dissipation of mitochondrial membrane potential, and cell death. Alternatively, inhibits the production of interferon in the infected cell at the level of host mitochondrial antiviral signaling MAVS. Its level of expression differs greatly depending on which cell type is infected, in a manner that is independent of the levels of expression of other viral proteins. Monocytic cells are more affected than epithelial cells. Seems to disable virus-infected monocytes or other host innate immune cells. During early stage of infection, predisposes the mitochondria to permeability transition through interaction with host SLC25A6/ANT3 and VDAC1. These proteins participate in the formation of the permeability transition pore complex (PTPC) responsible of the release of mitochondrial products that triggers apoptosis.SUBUNIT Oligomer. Interacts with human SLC25A6/ANT3 and VDAC1. Interacts with host MAVS.MISCELLANEOUS Is not encoded in all strains, and seems to be dispensable for replication.SIMILARITY Belongs to the influenza viruses PB1-F2 family.UniProtP0C0U1Reactome DB_ID: 497451mitochondrial inner membraneGO0005743UniProt:P12236 SLC25A6SLC25A6CDABP0051ANT3SLC25A6FUNCTION Catalyzes the exchange of cytoplasmic ADP with mitochondrial ATP across the mitochondrial inner membrane. May participate in the formation of the permeability transition pore complex (PTPC) responsible for the release of mitochondrial products that triggers apoptosis.SUBUNIT Found in a complex with ARL2, ARL2BP and SLC25A6 (By similarity). Homodimer.SUBUNIT (Microbial infection) Interacts with influenza A virus PB1-F2 protein.SUBUNIT (Microbial infection) Interacts with HIV-1 Vpr.DOMAIN The transmembrane helices are not perpendicular to the plane of the membrane, but cross the membrane at an angle. Odd-numbered transmembrane helices exhibit a sharp kink, due to the presence of a conserved proline residue.PTM Trimethylated by ANTKMT at Lys-52.MISCELLANEOUS The gene coding for this protein is located in the pseudoautosomal region 1 (PAR1) of X and Y chromosomes.SIMILARITY Belongs to the mitochondrial carrier (TC 2.A.29) family.UniProtP122362EQUAL298EQUALReactome DB_ID: 1692351PB1-F2: ANT 3 Complex [mitochondrial inner membrane]PB1-F2: ANT 3 ComplexReactome DB_ID: 51467891Reactome DB_ID: 4974512EQUAL298EQUALReactome Database ID Release 75169235Database 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=169235ReactomeR-HSA-1692354Reactome 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-169235.4Reactome Database ID Release 75168878Database 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=168878ReactomeR-HSA-1688785Reactome 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-168878.515163724Pubmed2004PB1-F2, an influenza A virus-encoded proapoptotic mitochondrial protein, creates variably sized pores in planar lipid membranesChanturiya, ANBasanez, GSchubert, UHenklein, PYewdell, JWZimmerberg, JJ Virol 78:6304-1211726970Pubmed2001A novel influenza A virus mitochondrial protein that induces cell deathChen, WCalvo, PAMalide, DGibbs, JSchubert, UBacik, IBasta, SO'Neill, RSchickli, JPalese, PHenklein, PBennink, JRYewdell, JWNat Med 7:1306-12Reactome Database ID Release 75168277Database 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=168277ReactomeR-HSA-1682775Reactome 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-168277.512021867Pubmed2002Exploitation of the Herpes simplex virus translocating protein VP22 to carry influenza virus proteins into cells for studies of apoptosis: direct confirmation that neuraminidase induces apoptosis and indications that other proteins may have a roleMorris, SJSmith, HSweet, CArch Virol 147:961-7911799156Pubmed2002NS1 protein of influenza A virus down-regulates apoptosisZhirnov, OPKonakova, TEWolff, TKlenk, HDJ Virol 76:1617-2511483732Pubmed2001Influenza virus ns1 protein induces apoptosis in cultured cellsSchultz-Cherry, SDybdahl-Sissoko, NNeumann, GKawaoka, YHinshaw, VSJ Virol 75:7875-817504071Pubmed1993Induction of programmed cell death (apoptosis) by influenza virus infection in tissue culture cellsTakizawa, TMatsukawa, SHiguchi, YNakamura, SNakanishi, YFukuda, RJ Gen Virol 74:2347-5515143063Pubmed2004NF-kappaB-dependent induction of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas/FasL is crucial for efficient influenza virus propagationWurzer, WJEhrhardt, CPleschka, SBerberich-Siebelt, FWolff, TWalczak, HPlanz, OLudwig, SJ Biol Chem 279:30931-70Pubmed2001Orthomyxoviridae: The Viruses and Their ReplicationPalese, PShaw, MLFields Virology, 5th edition D.M. Knipe and P.M. Howley, Editors. 2006, Lippencott Williams and Wilkins: Philadelphia ISBN-10: 0-7817-6060-71647-1689