BioPAX pathway converted from "DDX58/IFIH1-mediated induction of interferon-alpha/beta" in the Reactome database. DDX58/IFIH1-mediated induction of interferon-alpha/beta DDX58/IFIH1-mediated induction of interferon-alpha/beta RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> TRAF3-dependent IRF activation pathway TRAF3-dependent IRF activation pathway This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Dimerization of Phospho IRF3 or phospho IRF7 Dimerization of Phospho IRF3 or phospho IRF7 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 10217928 3 cytosol GO 0005829 p-4S,T404-IRF3,p-S477,S479-IRF7 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-IRF3 [cytosol] phospho-IRF7 [cytosol] Reactome http://www.reactome.org Sus scrofa NCBI Taxonomy 9823 UniProt Q764M6 UniProt F6PW48 Reactome DB_ID: 10247361 1 IRF3-P:IRF7-P [cytosol] IRF3-P:IRF7-P Reactome DB_ID: 10217922 1 UniProt:Q764M6 IRF3 O-phospho-L-serine at 396 (in Homo sapiens) 396 EQUAL O-phospho-L-serine [MOD:00046] O-phospho-L-serine at 398 (in Homo sapiens) 398 EQUAL O-phospho-L-serine at 402 (in Homo sapiens) 402 EQUAL O-phospho-L-serine at 405 (in Homo sapiens) 405 EQUAL O-phospho-L-threonine at 404 (in Homo sapiens) 404 EQUAL O-phospho-L-threonine [MOD:00047] Chain Coordinates 1 EQUAL 427 EQUAL Reactome DB_ID: 10217926 1 UniProt:F6PW48 IRF7 O-phospho-L-serine at 477 (in Homo sapiens) 477 EQUAL O-phospho-L-serine at 479 (in Homo sapiens) 479 EQUAL 1 EQUAL 503 EQUAL Reactome Database ID Release 81 10247361 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=10247361 Reactome R-SSC-1027367 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-SSC-1027367.1 Reactome DB_ID: 10218786 1 p-T,4S-IRF3:p-T,4S-IRF3 [cytosol] p-T,4S-IRF3:p-T,4S-IRF3 Reactome DB_ID: 10217922 2 O-phospho-L-serine at 396 (in Homo sapiens) 396 EQUAL O-phospho-L-serine at 398 (in Homo sapiens) 398 EQUAL O-phospho-L-serine at 402 (in Homo sapiens) 402 EQUAL O-phospho-L-serine at 405 (in Homo sapiens) 405 EQUAL O-phospho-L-threonine at 404 (in Homo sapiens) 404 EQUAL 1 EQUAL 427 EQUAL Reactome Database ID Release 81 10218786 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=10218786 Reactome R-SSC-166272 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-SSC-166272.1 Reactome DB_ID: 10218784 1 p-2S-IRF7:p-2S-IRF7 [cytosol] p-2S-IRF7:p-2S-IRF7 Reactome DB_ID: 10217926 2 O-phospho-L-serine at 477 (in Homo sapiens) 477 EQUAL O-phospho-L-serine at 479 (in Homo sapiens) 479 EQUAL 1 EQUAL 503 EQUAL Reactome Database ID Release 81 10218784 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=10218784 Reactome R-SSC-450344 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-SSC-450344.1 Reactome Database ID Release 81 10247373 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=10247373 Reactome R-SSC-1028821 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-SSC-1028821.1 Phosphorylation of these transcription factors IRF3 and IRF7 results in a conformational change that allows their dimerization to form homo- or hetero dimers. Each of the three different combinations of dimers (IRF3:IRF3, IRF7:IRF7 and IRF3:IRF7) may selectively effect the transcription of IFN-alpha gene subfamilies and IFN-beta genes. 12604599 Pubmed 2003 Interferon regulatory factor-7 synergizes with other transcription factors through multiple interactions with p300/CBP coactivators Yang, H Lin, CH Ma, G Baffi, MO Wathelet, MG J Biol Chem 278:15495-504 inferred by electronic annotation IEA GO IEA Translocation of phosphorylated IRF3,IRF7 dimers into nucleus Translocation of phosphorylated IRF3,IRF7 dimers into nucleus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10247361 1 Reactome DB_ID: 10218786 1 Reactome DB_ID: 10218784 1 Reactome DB_ID: 10247363 1 nucleoplasm GO 0005654 IRF3-P:IRF7-P [nucleoplasm] IRF3-P:IRF7-P Reactome DB_ID: 10220500 1 O-phospho-L-serine at 396 (in Homo sapiens) 396 EQUAL O-phospho-L-serine at 398 (in Homo sapiens) 398 EQUAL O-phospho-L-serine at 402 (in Homo sapiens) 402 EQUAL O-phospho-L-serine at 405 (in Homo sapiens) 405 EQUAL O-phospho-L-threonine at 404 (in Homo sapiens) 404 EQUAL 1 EQUAL 427 EQUAL Reactome DB_ID: 10220504 1 O-phospho-L-serine at 477 (in Homo sapiens) 477 EQUAL O-phospho-L-serine at 479 (in Homo sapiens) 479 EQUAL 1 EQUAL 503 EQUAL Reactome Database ID Release 81 10247363 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=10247363 Reactome R-SSC-1027365 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-SSC-1027365.1 Reactome DB_ID: 10220506 1 2xp-S477,S479-IRF7 [nucleoplasm] 2xp-S477,S479-IRF7 Reactome DB_ID: 10220504 2 O-phospho-L-serine at 477 (in Homo sapiens) 477 EQUAL O-phospho-L-serine at 479 (in Homo sapiens) 479 EQUAL 1 EQUAL 503 EQUAL Reactome Database ID Release 81 10220506 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=10220506 Reactome R-SSC-450306 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-SSC-450306.1 Reactome DB_ID: 10220502 1 p-T,4S-IRF3:p-T,4S-IRF3 [nucleoplasm] p-T,4S-IRF3:p-T,4S-IRF3 Reactome DB_ID: 10220500 2 O-phospho-L-serine at 396 (in Homo sapiens) 396 EQUAL O-phospho-L-serine at 398 (in Homo sapiens) 398 EQUAL O-phospho-L-serine at 402 (in Homo sapiens) 402 EQUAL O-phospho-L-serine at 405 (in Homo sapiens) 405 EQUAL O-phospho-L-threonine at 404 (in Homo sapiens) 404 EQUAL 1 EQUAL 427 EQUAL Reactome Database ID Release 81 10220502 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=10220502 Reactome R-SSC-177675 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-SSC-177675.1 Reactome Database ID Release 81 10247365 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=10247365 Reactome R-SSC-1028816 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-SSC-1028816.1 Phosphorylated IRF dimers after dimerization translocates into the nucleus and associate with general coactivators like CBP/p300 and bind to type-I IFN promoter region. inferred by electronic annotation IEA GO IEA CREBBP, EP300 binds p-T,4S-IRF3:p-T,4S-IRF3 CREBBP, EP300 binds p-T,4S-IRF3:p-T,4S-IRF3 Interaction of CBP/p300 with p-IRF3 dimer This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10220502 1 Converted from EntitySet in Reactome Reactome DB_ID: 10242890 1 CREBBP,EP300 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity EP300 [nucleoplasm] CREBBP [nucleoplasm] UniProt I3L9U8 UniProt F1RK46 Reactome DB_ID: 10247359 1 p-T,4S-IRF3:p-T,4S-IRF3:CREBBP, EP300 [nucleoplasm] p-T,4S-IRF3:p-T,4S-IRF3:CREBBP, EP300 Reactome DB_ID: 10220502 1 Converted from EntitySet in Reactome Reactome DB_ID: 10242890 1 Reactome Database ID Release 81 10247359 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=10247359 Reactome R-SSC-1027364 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-SSC-1027364.1 Reactome Database ID Release 81 10247367 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=10247367 Reactome R-SSC-1028817 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-SSC-1028817.1 Phosphorylated IRF3 dimer translocated to the nucleus interacts with the coactivator CBP/p300. This interaction prevents the export of activated IRF3 dimer from nucleus and it may also alter the conformation of the DNA binding domain of IRF3, and induce specific DNA binding of IRF3. 9541017 Pubmed 1998 Involvement of the IRF family transcription factor IRF-3 in virus-induced activation of the IFN-beta gene Sato, M Tanaka, N Hata, N Oda, E Taniguchi, T FEBS Lett 425:112-6 10082512 Pubmed 1999 Structural and functional analysis of interferon regulatory factor 3: localization of the transactivation and autoinhibitory domains Lin, R Mamane, Y Hiscott, J Mol Cell Biol 19:2465-74 9463386 Pubmed 1998 Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF-3 and CBP/p300 Yoneyama, M Suhara, W Fukuhara, Y Fukuda, M Nishida, E Fujita, T EMBO J 17:1087-95 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 81 10308275 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=10308275 Reactome R-SSC-918233 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-SSC-918233.1 MAVS via its TRAF-interaction motif (TIM) directly interacts with TRAF3 and recruits TRAF3 to the signaling complex. TRAF3 acts as a scaffold for the assembly of a signaling complex composed of IKK epsilon/TBK1, leading to the activation of transcription factors IRF3/IRF7. 16306936 Pubmed 2006 Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response Oganesyan, G Saha, SK Guo, B He, JQ Shahangian, A Zarnegar, B Perry, A Cheng, G Nature 439:208-11 17190786 Pubmed 2007 Antiviral signaling through pattern recognition receptors Kawai, T Akira, Shizuo J Biochem 141:137-45 inferred by electronic annotation IEA GO IEA TRAF6 mediated IRF7 activation TRAF6 mediated IRF7 activation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Dimerization of p-IRF7 Dimerization of p-IRF7 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10217926 2 O-phospho-L-serine at 477 (in Homo sapiens) 477 EQUAL O-phospho-L-serine at 479 (in Homo sapiens) 479 EQUAL 1 EQUAL 503 EQUAL Reactome DB_ID: 10218784 1 Reactome Database ID Release 81 10242884 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=10242884 Reactome R-SSC-933533 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-SSC-933533.1 Phosphorylation stimulates the C-terminal autoinhibitory domain of IRF7 to attain a highly extended conformation triggering dimerization through extensive contacts to a second IRF7 subunit. 11073981 Pubmed 2000 Phosphorylation-induced dimerization of interferon regulatory factor 7 unmasks DNA binding and a bipartite transactivation domain Marié, I Smith, E Prakash, A Levy, DE Mol Cell Biol 20:8803-14 20043992 Pubmed 2010 Structural insights into interferon regulatory factor activation Chen, W Royer WE, Jr Cell Signal 22:883-7 inferred by electronic annotation IEA GO IEA Translocation of p-IRF7:p-IRF7 to nucleus Translocation of p-IRF7:p-IRF7 to nucleus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10218784 1 Reactome DB_ID: 10220506 1 Reactome Database ID Release 81 10242882 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=10242882 Reactome R-SSC-933531 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-SSC-933531.1 p-IRF7 dimers are then transported into the nucleus and assemble with the coactivator CBP/p300 to activate transcription of type I interferons and other target genes. inferred by electronic annotation IEA GO IEA p-IRF7 dimer interacts with coactivator CBP/p300 p-IRF7 dimer interacts with coactivator CBP/p300 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10220506 1 Converted from EntitySet in Reactome Reactome DB_ID: 10242890 1 Reactome DB_ID: 10242892 1 CBP/p300:pIRF7:pIRF7 [nucleoplasm] CBP/p300:pIRF7:pIRF7 Reactome DB_ID: 10220506 1 Converted from EntitySet in Reactome Reactome DB_ID: 10242890 1 Reactome Database ID Release 81 10242892 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=10242892 Reactome R-SSC-933471 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-SSC-933471.1 Reactome Database ID Release 81 10242894 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=10242894 Reactome R-SSC-933536 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-SSC-933536.1 p-IRF7 dimers after translocation into nucleus interact with the coactivators p300 and CBP (CREB-binding protein) to form a stable complex. This interaction further increases the transcriptional activity of IRF7. inferred by electronic annotation IEA GO IEA Formation of VAF (virus-activated factor) complex Formation of VAF (virus-activated factor) complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10247363 1 Converted from EntitySet in Reactome Reactome DB_ID: 10242890 1 Reactome DB_ID: 10247369 1 VAF (virus-activated factor) [nucleoplasm] VAF (virus-activated factor) Reactome DB_ID: 10247363 1 Converted from EntitySet in Reactome Reactome DB_ID: 10242890 1 Reactome Database ID Release 81 10247369 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=10247369 Reactome R-SSC-1027360 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-SSC-1027360.1 Reactome Database ID Release 81 10247371 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=10247371 Reactome R-SSC-1028820 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-SSC-1028820.1 IRF3 and IRF7 associate with each other and they further interact with the coactivators CBP and p300 to form a more potent transcription factor complex called VAF (virus-activated factor). 9660935 Pubmed 1998 Virus infection induces the assembly of coordinately activated transcription factors on the IFN-beta enhancer in vivo Wathelet, MG Lin, CH Parekh, BS Ronco, LV Howley, PM Maniatis, T Mol Cell 1:507-18 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 81 10308207 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=10308207 Reactome R-SSC-933541 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-SSC-933541.1 TRAF6 is crucial for both RIG-I- and MDA5-mediated antiviral responses. The absence of TRAF6 resulted in enhanced viral replication and a significant reduction in the production of type I IFNs and IL6 after infection with RNA virus. Activation of NF-kB and IRF7, but not that of IRF3, was significantly impaired during RIG-like helicases (RLHs) signaling in the absence of TRAF6. TRAF6-induced activation of IRF is likely to be specific for IRF7, while TRAF3 is thought to activate both IRF3 and IRF7. These results strongly suggest that the TRAF6- and TRAF3-dependent pathways are likely to bifurcate at IPS-1, but to converge later at IRF7 in order to co-operatively induce sufficient production of type I IFNs during RLH signaling. 19479062 Pubmed 2009 TRAF6 establishes innate immune responses by activating NF-kappaB and IRF7 upon sensing cytosolic viral RNA and DNA Konno, H Yamamoto, T Yamazaki, K Gohda, J Akiyama, T Semba, K Goto, H Kato, A Yujiri, T Imai, T Kawaguchi, Y Su, B Takeuchi, O Akira, Shizuo Tsunetsugu-Yokota, Y Inoue, J PLoS One 4:e5674 inferred by electronic annotation IEA GO IEA TRAF6 mediated NF-kB activation TRAF6 mediated NF-kB activation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2.7.11.1 Active IKK Complex phosphorylates NF-kappa-B inhibitor Active IKK Complex phosphorylates NF-kappa-B inhibitor This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10218542 1 NFkB inhibitor:NFkB complex [cytosol] NFkB inhibitor:NFkB complex Reactome DB_ID: 10218530 1 NFKB1(1-433), NFKB2(1-454):RELA [cytosol] NFKB1(1-433), NFKB2(1-454):RELA Converted from EntitySet in Reactome Reactome DB_ID: 10218528 1 NFKB1(1-433), NFKB2(1-454) [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity NFKB1 [cytosol] NFKB2 [cytosol] UniProt A0A287AVR3 UniProt F1S861 Reactome DB_ID: 10218518 1 UniProt:F6PVF4 RELA UniProt F6PVF4 1 EQUAL 551 EQUAL Reactome Database ID Release 81 10218530 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=10218530 Reactome R-SSC-168155 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-SSC-168155.1 Converted from EntitySet in Reactome Reactome DB_ID: 10218540 1 NFkB inhibitor [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity NFKBIA [cytosol] NFKBIB [cytosol] UniProt Q08353 UniProt I3LLS5 Reactome Database ID Release 81 10218542 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=10218542 Reactome R-SSC-168130 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-SSC-168130.1 Reactome DB_ID: 113592 4 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 10218530 1 Converted from EntitySet in Reactome Reactome DB_ID: 10218552 1 Phospho-NF-kappaB Inhibitor [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-NFKBIB [cytosol] phospho-NFKBIA [cytosol] Reactome DB_ID: 29370 4 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10218570 IKBKG:p-S176,S180-CHUK:p-S177,S181-IKBKB [cytosol] IKBKG:p-S176,S180-CHUK:p-S177,S181-IKBKB Reactome DB_ID: 10218556 1 UniProt:A9QT41 IKBKG UniProt A9QT41 1 EQUAL 419 EQUAL Reactome DB_ID: 10218568 1 UniProt:A0A287A5Q1 IKBKB UniProt A0A287A5Q1 O-phospho-L-serine at 177 (in Homo sapiens) 177 EQUAL O-phospho-L-serine at 181 (in Homo sapiens) 181 EQUAL 1 EQUAL 756 EQUAL Reactome DB_ID: 10218562 1 UniProt:F1S8V5 CHUK UniProt F1S8V5 O-phospho-L-serine at 176 (in Homo sapiens) 176 EQUAL O-phospho-L-serine at 180 (in Homo sapiens) 180 EQUAL 1 EQUAL 745 EQUAL Reactome Database ID Release 81 10218570 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=10218570 Reactome R-SSC-177663 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-SSC-177663.1 GO 0004674 GO molecular function Reactome Database ID Release 81 10218571 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=10218571 Reactome Database ID Release 81 10218583 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=10218583 Reactome R-SSC-168140 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-SSC-168140.1 In human, IkBs (NFKBIA, NFKBIB or NFKBIE) are inhibitory proteins that sequesters NF-kappa-B in the cytoplasm, by masking a nuclear localization signal, located just at the C-terminal end of the RelA (p65) subunit of the RelA:NFKB1 heterodimer. <p>A key event in NF-kappa-B activation involves phosphorylation of IkB by an IkB kinase (IKK). The phosphorylation and ubiquitination of IkB kinase complex is mediated by two distinct pathways, either the classical or alternative pathway. In the classical NF-kappa-B signaling pathway, the activated IKK (IkB kinase) complex, predominantly acting through IKK beta (IKKb, IKBKB) in an IKK gamma (IKBKG, NEMO)-dependent manner, catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of human NFKBIA (IkB-alpha) or Ser19 and Ser22 of NFKBIB (IkB-beta)). Once phosphorylated, IkB undergoes ubiquitin-mediated degradation, releasing NF-kappa-B.<br> 12221085 Pubmed 2002 IKKalpha, IKKbeta, and NEMO/IKKgamma are each required for the NF-kappa B-mediated inflammatory response program Li, X Massa, PE Hanidu, A Peet, GW Aro, P Savitt, A Mische, S Li, J Marcu, KB J Biol Chem 277:45129-40 19666475 Pubmed 2009 The nemo binding domains of both IKKalpha and IKKbeta regulate IKK complex assembly and classical NFkappaB activation Solt, LA Madge, LA May, MJ J Biol Chem 27701768 Pubmed 2017 Double phosphorylation-induced structural changes in the signal-receiving domain of IκBα in complex with NF-κB Yazdi, Samira Naumann, Michael Stein, Matthias Proteins 85:17-29 10723127 Pubmed 2000 Activation of NF-kappa B by the dsRNA-dependent protein kinase, PKR involves the I kappa B kinase complex Gil, J Alcami, J Esteban, M Oncogene 19:1369-78 17047224 Pubmed 2006 Regulation and function of IKK and IKK-related kinases Hacker, H Karin, M Sci STKE 2006:re13 inferred by electronic annotation IEA GO IEA INHIBITION Reactome Database ID Release 81 10218584 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=10218584 Converted from EntitySet in Reactome Reactome DB_ID: 10218581 NKIRAS [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity NKIRAS1 [cytosol] NKIRAS2 [cytosol] UniProt I3L911 UniProt F2Z555 NF-kappa-B complex is transported from cytosol to nucleus NF-kappa-B complex is transported from cytosol to nucleus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10218530 1 Reactome DB_ID: 10218625 1 NFkB Complex [nucleoplasm] NFkB Complex Reactome DB_ID: 10218623 1 1 EQUAL 551 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10218621 1 Nuclear factor NF-kappa-B [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity NFKB2 [nucleoplasm] NFKB1 [nucleoplasm] Reactome Database ID Release 81 10218625 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=10218625 Reactome R-SSC-177673 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-SSC-177673.1 Reactome Database ID Release 81 10218673 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=10218673 Reactome R-SSC-168166 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-SSC-168166.1 NFkB is a family of transcription factors that play pivotal roles in immune, inflammatory, and antiapoptotic responses. There are five NF-kB/Rel family members, p65 (RelA), RelB, c-Rel, p50/p105 (NF-kappa-B1) and p52/p100 (NF-kappa-B2). All members of the NFkB family contain a highly conserved DNA-binding and dimerization domain called Rel-homology region (RHR). The RHR is responsible for homo- or heterodimerization. Therefore, NF-kappa-B exists in unstimulated cells as homo or heterodimers; the most common heterodimer is p65/p50. NF-kappa-B is sequestered in the cytosol of unstimulated cells through the interactions with a class of inhibitor proteins called IkBs, which mask the nuclear localization signal of NF-kB and prevent its nuclear translocation. Various stimuli induce the activation of the IkB kinase (IKK) complex, which then phosphorylates IkBs. The phosphorylated IkBs are ubiquitinated and then degraded through the proteasome-mediated pathway. The degradation of IkBs releases NF-kappa-B and and it can be transported into nucleus where it induces the expression of target genes.<br> 16056267 Pubmed 2005 Ubiquitin signalling in the NF-kappaB pathway Chen, ZJ Nat Cell Biol 7:758-65 15145317 Pubmed 2004 The two NF-kappaB activation pathways and their role in innate and adaptive immunity Bonizzi, G Karin, M Trends Immunol 25:280-8 inferred by electronic annotation IEA GO IEA ACTIVATION Reactome Database ID Release 81 10218674 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=10218674 Reactome DB_ID: 10218671 plasma membrane GO 0005886 AGER ligands:AGER [plasma membrane] AGER ligands:AGER Reactome DB_ID: 10218629 1 UniProt:F6PXJ4 AGER UniProt F6PXJ4 23 EQUAL 404 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10218669 1 extracellular region GO 0005576 AGER ligands [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity APP [extracellular region] APP [extracellular region] APP [extracellular region] APP [extracellular region] HMGB1 [extracellular region] UniProt P79307 UniProt A0A288CFW8 UniProt A0A287BEI7 Reactome Database ID Release 81 10218671 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=10218671 Reactome R-SSC-879365 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-SSC-879365.1 Reactome Database ID Release 81 10307083 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=10307083 Reactome R-SSC-933542 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-SSC-933542.1 The TRAF6/TAK1 signal activates a canonical IKK complex, resulting in the activation of NF-kB as well as MAPK cascades leading to the activation of AP-1. Although TRAF6/TAK1 has been implicated in Tool like receptor (TLR) mediated cytokine production, the involvement of these molecules in the regulation of type I IFN induction mediated by RIG-I/MDA5 pathway is largely unknown. According to the study done by Yoshida et al RIG-I/IPS-1 pathway requires TRAF6 and MAP3K, MEKK1 to activate NF-kB and MAP Kinases for optimal induction of type I IFNs. 18984593 Pubmed 2008 TRAF6 and MEKK1 play a pivotal role in the RIG-I-like helicase antiviral pathway Yoshida, R Takaesu, G Yoshida, H Okamoto, F Yoshioka, T Choi, Y Akira, Shizuo Kawai, T Yoshimura, A Kobayashi, T J Biol Chem 283:36211-20 inferred by electronic annotation IEA GO IEA Negative regulators of DDX58/IFIH1 signaling Negative regulators of DDX58/IFIH1 signaling Negative regulators of RIG-I/MDA5 signaling This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Interaction of PIN1 with p-IRF3 Interaction of PIN1 with p-IRF3 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10242931 1 UniProt:I3LLH5 PIN1 UniProt I3LLH5 1 EQUAL 163 EQUAL Reactome DB_ID: 10242936 1 p-IRF3:p-IRF3 [nucleoplasm] p-IRF3:p-IRF3 Reactome DB_ID: 10242934 2 O-phospho-L-serine at 396 (in Homo sapiens) 396 EQUAL O-phospho-L-serine at 398 (in Homo sapiens) 398 EQUAL O-phospho-L-serine at 402 (in Homo sapiens) 402 EQUAL O-phospho-L-serine at 405 (in Homo sapiens) 405 EQUAL O-phospho-L-threonine at 404 (in Homo sapiens) 404 EQUAL O-phospho-L-serine at 339 (in Homo sapiens) 339 EQUAL 1 EQUAL 427 EQUAL Reactome Database ID Release 81 10242936 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=10242936 Reactome R-SSC-936446 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-SSC-936446.1 Reactome DB_ID: 10242938 1 p-IRF3 dimer:PIN1 [nucleoplasm] p-IRF3 dimer:PIN1 Reactome DB_ID: 10242931 1 1 EQUAL 163 EQUAL Reactome DB_ID: 10242936 1 Reactome Database ID Release 81 10242938 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=10242938 Reactome R-SSC-936444 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-SSC-936444.1 Reactome Database ID Release 81 10242940 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=10242940 Reactome R-SSC-936380 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-SSC-936380.1 Two cluster of serine residues in the C-terminus of IRF3 are essential for its activation. Cluster 1, comprising Ser385 and Ser386, is essential for the formation of IRF3 dimers. The second cluster include a series of serine and threonine residues between Ser396 and Ser405. Phosphorylation of residues in both clusters has been noted in response to virus infection and dsRNA treatment, and the IKKi/TBK1 kinase complex has been shown to phosphorylate both clusters. <br>Yamaoka et al has shown that IRF3 is also phosphorylated on Ser339 after dsRNA stimulation, however this phosphorylation is associated with destabilization rather than activation of IRF3. This Ser339 precedes a proline residue 340 (Pro340) and this serine-proline motif acts as a binding site for the protein PIN1, a peptidyl-prolyl-isomerase. PIN1 consist of two distinct domains, a short N-terminal WW domain and a C-terminal catalytic domain. The WW domain of PIN1 is involved in binding the ser339-pro340 region. Yamaoka et al showed that exogenous expression of PIN1 suppresses IRF3 activation and type I interferon production and, conversely, that siRNA silencing of PIN1 leads to enhancement of IRF3 activation and IFNB production. 19125153 Pubmed 2009 Inhibition of IRF3-dependent antiviral responses by cellular and viral proteins Tsuchida, T Kawai, T Akira, Shizuo Cell Res 19:3-4 16715065 Pubmed 2006 Pin-ning down immune responses to RNA viruses Goutagny, N Severa, M Fitzgerald, Katherine A Nat Immunol 7:555-7 16699525 Pubmed 2006 Negative regulation of interferon-regulatory factor 3-dependent innate antiviral response by the prolyl isomerase Pin1 Saitoh, T Tun-Kyi, A Ryo, A Yamamoto, M Finn, G Fujita, T Akira, Shizuo Yamamoto, N Lu, KP Yamaoka, S Nat Immunol 7:598-605 inferred by electronic annotation IEA GO IEA CYLD mediated deubiquitination of DDX58 (RIG-I) CYLD mediated deubiquitination of DDX58 (RIG-I) This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10242947 1 UniProt:A0A287AMJ0 DDX58 UniProt A0A287AMJ0 ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 154 (in Homo sapiens) 154 EQUAL ubiquitinylated lysine [MOD:01148] ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 164 (in Homo sapiens) 164 EQUAL ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 172 (in Homo sapiens) 172 EQUAL 1 EQUAL 925 EQUAL Reactome DB_ID: 10242949 1 1 EQUAL 925 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10206582 1 Ub [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity RPS27A [cytosol] UBA52 [cytosol] UBC [cytosol] UniProt A0A287AZA7 UniProt P63053 UniProt P0CG68 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10215408 UniProt:A0A287ACG0 CYLD UniProt A0A287ACG0 1 EQUAL 956 EQUAL GO 0061578 GO molecular function Reactome Database ID Release 81 10242950 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=10242950 Reactome Database ID Release 81 10242952 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=10242952 Reactome R-SSC-936390 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-SSC-936390.1 CYLD is an ovarian tumor (OTU) domain-containing deubiquitinating enzyme (DUB) and has been identified as a negative regulator of DDX58 (RIG-I) mediated antiviral signaling. CYLD associates with the CARD domain of DDX58 and removes K63-linked ubiquitin from the DDX58 CARDs that are conjugated by the E3 ubiquitin ligase, TRIM25 and RNF135. 18467330 Pubmed 2008 Regulation of IkappaB kinase-related kinases and antiviral responses by tumor suppressor CYLD Zhang, M Wu, X Lee, AJ Jin, W Chang, M Wright, A Imaizumi, T Sun, SC J Biol Chem 283:18621-6 18636086 Pubmed 2008 The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response Friedman, CS O'Donnell, MA Legarda-Addison, D Ng, A Cardenas, Washington B Yount, JS Moran, TM Basler, CF Komuro, A Horvath, CM Xavier, R Ting, AT EMBO Rep 9:930-6 inferred by electronic annotation IEA GO IEA ISGylation of DDX58 ISGylation of DDX58 ISGylation of RIG-I This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10242949 1 1 EQUAL 925 EQUAL Reactome DB_ID: 10242972 1 ISG15:UBEIL/UbcH8:CEB1 [cytosol] ISG15:UBEIL/UbcH8:CEB1 Reactome DB_ID: 10242956 1 UniProt:I3LA49 HERC5 UniProt I3LA49 1 EQUAL 1024 EQUAL Reactome DB_ID: 10242960 1 UniProt:A0A287AB58 ISG15 UniProt A0A287AB58 2 EQUAL 157 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10242970 1 E2 enzymes UbcH8/UBE1L [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity UBA7 [cytosol] UBE2L6 [cytosol] UniProt A0A287AYD1 UniProt I3LMJ6 Reactome Database ID Release 81 10242972 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=10242972 Reactome R-SSC-936560 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-SSC-936560.1 Reactome DB_ID: 10242974 1 ISG15:DDX58 conjugate [cytosol] ISG15:DDX58 conjugate Reactome DB_ID: 10242949 1 1 EQUAL 925 EQUAL Reactome DB_ID: 10242972 1 Reactome Database ID Release 81 10242974 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=10242974 Reactome R-SSC-936557 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-SSC-936557.1 Reactome Database ID Release 81 10242976 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=10242976 Reactome R-SSC-936563 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-SSC-936563.1 ISG15 is an ubiquitin (Ub)-like protein which is conjugated to intracellular proteins via an isopeptide bond. Similar to ubiquitination, the conjugation of ISG15 (ISGylation) requires a three-step process, involving an E1 activating enzyme (UBE1L), an E2 conjugating enzyme (UbcM8/H8), and HERC5/Ceb1 an IFN-inducible ISG15-specific E3 ligase. ISG15 conjugation may play an important regulatory role in IFN-mediated antiviral responses. IFN induces ISG15 conjugation to DDX58 negatively regulating DDX58-mediated antiviral signaling. ISGylated DDX58 becomes subject to an irreversible biochemical process, such as proteolysis or proteasomeal degradation. 18057259 Pubmed 2008 Negative feedback regulation of RIG-I-mediated antiviral signaling by interferon-induced ISG15 conjugation Kim, MJ Hwang, SY Imaizumi, T Yoo, JY J Virol 82:1474-83 inferred by electronic annotation IEA GO IEA TAX1BP1:A20 inhibit TBK1/IKKi K63-polyubiquitination TAX1BP1:A20 inhibit TBK1/IKKi K63-polyubiquitination This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10243160 1 TAX1BP1:TNFAIP3 [cytosol] TAX1BP1:TNFAIP3 Reactome DB_ID: 10243158 1 UniProt:K7GLC2 TAX1BP1 UniProt K7GLC2 1 EQUAL 789 EQUAL Reactome DB_ID: 10215412 1 UniProt:F1S6A4 TNFAIP3 UniProt F1S6A4 1 EQUAL 790 EQUAL Reactome Database ID Release 81 10243160 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=10243160 Reactome R-SSC-937339 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-SSC-937339.1 Converted from EntitySet in Reactome Reactome DB_ID: 10243068 1 TBK1, IKBKE [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity IKBKE [cytosol] TBK1 [cytosol] UniProt M9MMN5 UniProt A7UNK0 Reactome DB_ID: 10243162 1 TAX1BP1:TNFAIP3:TBK1/IKKi [cytosol] TAX1BP1:TNFAIP3:TBK1/IKKi Converted from EntitySet in Reactome Reactome DB_ID: 10243068 1 Reactome DB_ID: 10243160 1 Reactome Database ID Release 81 10243162 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=10243162 Reactome R-SSC-937333 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-SSC-937333.1 Reactome Database ID Release 81 10243164 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=10243164 Reactome R-SSC-937337 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-SSC-937337.1 TAX1BP1 functions as an adaptor molecule for A20 to terminate antiviral signaling. TAX1BP1 and A20 blocked antiviral signaling by disrupting K63-linked polyubiquitination of TBK1-IKKi. 20304918 Pubmed 2010 TAX1BP1 and A20 inhibit antiviral signaling by targeting TBK1-IKKi kinases Parvatiyar, K Barber, GN Harhaj, EW J Biol Chem 285:14999-5009 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 81 10308221 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=10308221 Reactome R-SSC-936440 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-SSC-936440.1 GO 0032480 GO biological process As with other cytokine systems, production of type I IFN is a transient process, and can be hazardous to the host if unregulated, resulting in chronic cellular toxicity or inflammatory and autoimmune diseases. RIG-I-mediated production of IFN can, in turn, increase the transcription of RIG-I itself, thus setting into motion an IFN amplification loop, which if left unchecked, could become deleterious to the host. This module mainly focuses on the endogenous negative regulation of the RIG-I-like receptor (RLR) family proteins RIG-I and MDA5. 18703349 Pubmed 2008 Negative regulation of cytoplasmic RNA-mediated antiviral signaling Komuro, A Bamming, D Horvath, CM Cytokine 43:350-8 18549796 Pubmed 2008 Regulation of mitochondrial antiviral signaling pathways Moore, CB Ting, JP Immunity 28:735-9 inferred by electronic annotation IEA GO IEA HSP90 binds TBK1 and IRF3 HSP90 binds TBK1 and IRF3 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 10266483 1 HSP90:HSP90 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 10217907 1 2 EQUAL 427 EQUAL Reactome DB_ID: 10243066 1 UniProt:A7UNK0 TBK1 1 EQUAL 729 EQUAL Reactome DB_ID: 10304812 1 HSP90:TBK1:IRF3 [cytosol] HSP90:TBK1:IRF3 Converted from EntitySet in Reactome Reactome DB_ID: 10266483 1 Reactome DB_ID: 10217907 1 2 EQUAL 427 EQUAL Reactome DB_ID: 10243066 1 1 EQUAL 729 EQUAL Reactome Database ID Release 81 10304812 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=10304812 Reactome R-SSC-9709836 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-SSC-9709836.1 Reactome Database ID Release 81 10304814 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=10304814 Reactome R-SSC-9709831 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-SSC-9709831.1 During viral infection, cytosolic viral RNA triggers activation of mitochondrial antiviral-signaling protein (MAVS) and the formation of MAVS signalosome (Kawai T et al. 2005; Seth RB et al. 2005; Xu LG et al. 2005). Activated MAVS recruits TANK-binding kinase 1 (TBK1), interferon regulatory factor 3 (IRF3) and IRF7 to the mitochondria leading to the activation of IRF3/IRF7 and subsequent production of type I interferons (Kawai T et al. 2005; Seth RB et al. 2005; Xu LG et al. 2005).<p>Co-immunoprecipitation assay showed that both TBK1 and IRF3 associated with heat shock protein 90kDa (HSP90), which facilitated signal transduction from TBK1 to IRF3 in Sendai virus (SeV)-infected human embryonic kidney (HEK293) cells (Yang K et l. 2006). MAVS, TBK1 and IRF3 were found to associate with mitochondrial import receptor subunit TOM70 (TOMM70) in HEK293 cells (Liu XY et al. 2010). TOMM70 localizes on the outer membrane of the mitochondria to mediate the translocation of mitochondrial protein precursors from the cytosol into the mitochondria (reviewed in Fan AC & Young JC 2011; Sokol AM et al. 2014; Kreimendahl S & Rassow J 2020). The molecular chaperone complexes of HSP90 and HSP70 were shown to deliver precursor proteins to TOMM70 for subsequent import (Young JC et al. 2003; Zanphorlin LM et al. 2016). The C-terminal motif (EEVD) of HSP90 was found to bind the N-terminal TPR clamp-type domain of TOMM70 (Liu XY et al. 2010; Gava LM et al. 2011). Knockdown of HSP90 by small interfering RNA (siRNA) decreased the association of TOMM70 with TBK1 and IRF3 in HEK293T cells (Liu XY et al. 2010). Further, in SeV-stimulated HEK293 cells, cytosolic BAX translocated to the mitochondrial outer membrane and induced apoptosis in the IRF3-dependent manner via the formation of the TOMM70:HSP90:IRF3:BAX protein complex (Wei B et al. 2015). The data suggest that HSP90 forms a complex with TBK1 and IRF3 in the cytosol and deliver them to the MAVS signalosome on the mitochondria.<p>Interaction between HSP90 and US11, a viral protein derived from human herpesvirus 1 (HHV-1, also known as herpes simplex virus 1, HSV-1) disrupted the formation of the HSP90:TBK1:IRF3 complex and induced degradation of TBK1 through a proteasome-dependent pathway in mouse embryonic fibroblasts (MEFs) (Liu X et al. 2018). 16394098 Pubmed 2006 Hsp90 regulates activation of interferon regulatory factor 3 and TBK-1 stabilization in Sendai virus-infected cells Yang, Kai Shi, Hexin Qi, Rong Sun, Shaogang Tang, Yujie Zhang, Bianhong Wang, Chen Mol Biol Cell 17:1461-71 24866464 Pubmed 2014 Mitochondrial protein translocases for survival and wellbeing Sokol, Anna Magdalena Sztolsztener, Malgorzata Eliza Wasilewski, Michal Heinz, Eva Chacinska, Agnieszka FEBS Lett 588:2484-95 25609812 Pubmed 2015 Tom70 mediates Sendai virus-induced apoptosis on mitochondria Wei, Bo Cui, Ye Huang, Yuefeng Liu, Heng Li, L Li, Mi Ruan, Kang-Cheng Zhou, Qin Wang, Chen J Virol 89:3804-18 21781956 Pubmed 2011 Stoichiometry and thermodynamics of the interaction between the C-terminus of human 90kDa heat shock protein Hsp90 and the mitochondrial translocase of outer membrane Tom70 Gava, Lisandra M Gonçalves, Danieli C Borges, Júlio C Ramos, Carlos H I Arch Biochem Biophys 513:119-25 16125763 Pubmed 2005 Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3 Seth, RB Sun, L Ea, CK Chen, ZJ Cell 122:669-82 16153868 Pubmed 2005 VISA is an adapter protein required for virus-triggered IFN-beta signaling Xu, LG Wang, YY Han, KJ Li, LY Zhai, Z Shu, HB Mol Cell 19:727-40 27402847 Pubmed 2016 Heat Shock Protein 90 kDa (Hsp90) Has a Second Functional Interaction Site with the Mitochondrial Import Receptor Tom70 Zanphorlin, Leticia M Lima, Tatiani B Wong, Michael J Balbuena, Tiago S Minetti, Conceição A S A Remeta, David P Young, Jason C Barbosa, Leandro R S Gozzo, Fabio C Ramos, Carlos H I J Biol Chem 291:18620-31 12526792 Pubmed 2003 Molecular chaperones Hsp90 and Hsp70 deliver preproteins to the mitochondrial import receptor Tom70 Young, Jason C Hoogenraad, Nicholas J Hartl, F Ulrich Cell 112:41-50 33019591 Pubmed 2020 The Mitochondrial Outer Membrane Protein Tom70-Mediator in Protein Traffic, Membrane Contact Sites and Innate Immunity Kreimendahl, Sebastian Rassow, Joachim Int J Mol Sci 21: 29743370 Pubmed 2018 Herpes Simplex Virus 1 Inhibits TANK-Binding Kinase 1 through Formation of the Us11-Hsp90 Complex Liu, Xing Main, David Ma, Yijie He, Bin J Virol 92: 20628368 Pubmed 2010 Tom70 mediates activation of interferon regulatory factor 3 on mitochondria Liu, Xin-Yi Wei, Bo Shi, He-Xin Shan, Yu-Fei Wang, Chen Cell Res 20:994-1011 16127453 Pubmed 2005 IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction Kawai, T Takahashi, K Sato, S Coban, C Kumar, H Kato, H Ishii, KJ Takeuchi, O Nat Immunol 6:981-8 inferred by electronic annotation IEA GO IEA MAVS binds TOMM70 MAVS binds TOMM70 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10242980 1 mitochondrial outer membrane GO 0005741 UniProt:F1S8C6 MAVS UniProt F1S8C6 1 EQUAL 540 EQUAL Reactome DB_ID: 10269318 1 UniProt:A0A480UKD4 TOMM70 UniProt A0A480UKD4 2 EQUAL 608 EQUAL Reactome DB_ID: 10304816 1 MAVS:TOMM70 [mitochondrial outer membrane] MAVS:TOMM70 Reactome DB_ID: 10242980 1 1 EQUAL 540 EQUAL Reactome DB_ID: 10269318 1 2 EQUAL 608 EQUAL Reactome Database ID Release 81 10304816 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=10304816 Reactome R-SSC-9709860 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-SSC-9709860.1 Reactome Database ID Release 81 10304818 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=10304818 Reactome R-SSC-9709842 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-SSC-9709842.1 Mitochondrial import receptor subunit TOM70 (TOMM70) recognizes mitochondrial protein precursors in the cytosol and mediates their transition to the mitochondrial compartments (reviewed in Fan ACY & Young JC et al. 2011; Sokol AM et al. 2014; Kreimendahl S & Rassow J 2020). The molecular chaperone complexes of heat shock protein 90 kDa (HSP90) and HSP70 deliver precursor proteins to TOMM70 for subsequent import (Young JC et al. 2003; Zanphorlin LM et al. 2016).<p>During viral infection, cytosolic viral RNA triggers activation of mitochondrial antiviral-signaling protein (MAVS) and the formation of MAVS signalosome (Kawai T et al. 2005; Seth RB et al. 2005; Xu LG et al. 2005). MAVS localizes on the outer membrane of mitochondria through its C-terminal transmembrane (TM) domain. Activated MAVS recruits TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) to mitochondria leading to the activation of IRF3 and subsequent production of type I interferons.<p>Immunoprecipitation assays coupled to mass spectrometry analysis revealed that TOMM70 interacted with exogenously expressed MAVS in Sendai virus (SeV)-stimulated human embryonic kidney (HEK293) cells (Liu XY et al. 2010). The TM domains of both MAVS and TOMM70 were required for their interaction. In addition, TOMM70 interacted strongly with the C-terminal motif (EEVD) of HSP90 (Liu XY et al. 2010; Gava LM et al. 2011). TOMM70 also co-immunoprecipitated with TBK1 and IRF3 in HEK293 cells (Liu XY et al. 2010). Further, both TBK1 and IRF3 were found to associate with HSP90, which facilitated signal transduction from TBK1 to IRF3 in SeV-infected HEK293 cells (Yang K et l. 2006). Moreover, SeV infection enhanced the interaction between IRF3 and apoptosis regulator BAX (BAX) in HEK293T cells (Wei B et al. 2015). In SeV-stimulated HEK293 cells, cytosolic BAX translocated to the mitochondrial outer membrane and induced apoptosis in the IRF3-dependent manner via the formation of the TOMM70:HSP90:IRF3:BAX protein complex (Wei B et al. 2015). Knockdown of HSP90 by small interfering RNA (siRNA) decreased the association of TOMM70 with TBK1 and IRF3 (Liu XY et al. 2010). Overexpression of TOMM70 enhanced mRNA levels of IRF3-responsive genes (including IFNB, IFIT1 and RANTES) in HEK293 cells during SeV infection or poly(I:C) stimulation, whereas knockdown of TOMM70 by siRNA showed an inhibitory effect. Similar results were obtained in murine bone marrow-derived macrophages and bone marrow-derived dendritic cells (Liu XY et al. 2010). Thus, the association of MAVS with TOMM70 is thought to potentiate the HSP90-mediated recruitment of TBK1and IRF3 to mitochondria during viral infection thereby inducing IRF3-mediated host antiviral responses. In addition, binding of MAVS to TOMM70 can also trigger BAX-dependent apoptosis (Wei B et al. 2015). TOMM70 also associated with TRADD, TRAF6 and STING in HEK293 cells, further indicating that TOMM70 is a component of MAVS signal complex on mitochondria (Liu XY et al. 2010).<p>The viral orf9b (9b) proteins derived from SARS‑CoV-1 and SARS-CoV-2 inhibit the MAVS-mediated production of type I IFNs by targeting TOMM70 on the mitochondria (Jiang HW et al. 2020).<p>This Reactome event shows the association of MAVS with TOMM70. 20955164 Pubmed 2011 Function of cytosolic chaperones in Tom70-mediated mitochondrial import Fan, Anna C Y Young, Jason C Protein Pept Lett 18:122-31 32728199 Pubmed 2020 SARS-CoV-2 Orf9b suppresses type I interferon responses by targeting TOM70 Jiang, He-Wei Zhang, Hai-Nan Meng, Qing-Feng Xie, Jia Li, Yang Chen, Hong Zheng, Yun-Xiao Wang, Xue-Ning Qi, Huan Zhang, Jing Wang, Pei-Hui Han, Ze-Guang Tao, Sheng-Ce Cell Mol Immunol 17:998-1000 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 81 10307085 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=10307085 Reactome R-SSC-168928 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-SSC-168928.1 RIG-I-like helicases (RLHs) the retinoic acid inducible gene-I (RIG-I) and melanoma differentiation associated gene 5 (MDA5) are RNA helicases that recognize viral double-stranded RNA (dsRNA) present within the cytoplasm (Yoneyama M & Fujita T 2007, 2008). Upon viral infection dsRNA is generated by positive-strand RNA virus families such as Flaviviridae and Coronaviridae, negative-strand RNA virus families including Orthomyxoviridae and Paramyxoviridae, and DNA virus families such as Herpesviridae and Adenoviridae (Weber F et al. 2006; Son KN et al. 2015). Functionally RIG-I and MDA5 positively regulate the IFN genes in a similar fashion, however they differ in their response to different viral species. RIG-I is essential for detecting influenza virus, Sendai virus, VSV and Japanese encephalitis virus (JEV), whereas MDA5 is essential in sensing encephalomyocarditis virus (EMCV), Mengo virus and Theiler's virus, all of which belong to the picornavirus family. RIG-I and MDA5 signalling results in the activation of IKK epsilon and (TKK binding kinase 1) TBK1, two serine/threonine kinases that phosphorylate interferon regulatory factor 3 and 7 (IRF3 and IRF7). Upon phosphorylation, IRF3 and IRF7 translocate to the nucleus and subsequently induce interferon alpha (IFNA) and interferon beta (IFNB) gene transcription (Yoneyama M et al. 2004; Yoneyama M & Fujita T 2007, 2008). 15208624 Pubmed 2004 The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses Yoneyama, M Kikuchi, M Natsukawa, T Shinobu, N Imaizumi, T Miyagishi, M Taira, K Fujita, T Nat Immunol 5:730-7 26136565 Pubmed 2015 Double-Stranded RNA Is Detected by Immunofluorescence Analysis in RNA and DNA Virus Infections, Including Those by Negative-Stranded RNA Viruses Son, Kyung-No Liang, Zhiguo Lipton, Howard L J. Virol. 89:9383-92 17683970 Pubmed 2007 RIG-I family RNA helicases: cytoplasmic sensor for antiviral innate immunity Yoneyama, M Fujita, T Cytokine Growth Factor Rev 18:545-51 18701081 Pubmed 2008 Structural mechanism of RNA recognition by the RIG-I-like receptors Yoneyama, M Fujita, T Immunity 29:178-81 16641297 Pubmed 2006 Double-stranded RNA is produced by positive-strand RNA viruses and DNA viruses but not in detectable amounts by negative-strand RNA viruses Weber, Friedemann Wagner, Valentina Rasmussen, Simon B Hartmann, Rune Paludan, Søren R J Virol 80:5059-64 17942531 Pubmed 2008 Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity Loo, YM Fornek, J Crochet, N Bajwa, G Perwitasari, O Martinez-Sobrido, L Akira, Shizuo Gill, MA Garcia-Sastre, A Katze, MG Gale M, Jr J Virol 82:335-45 18989317 Pubmed 2008 Viral evasion and subversion of pattern-recognition receptor signalling Bowie, AG Unterholzner, L Nat Rev Immunol 8:911-22 16214811 Pubmed 2005 Regulation of the type I IFN induction: a current view Honda, K Yanai, H Takaoka, A Taniguchi, T Int Immunol 17:1367-78 17395582 Pubmed 2007 Function of RIG-I-like receptors in antiviral innate immunity Yoneyama, M Fujita, T J Biol Chem 282:15315-8 inferred by electronic annotation IEA GO IEA