ID   IFIH1_HUMAN             Reviewed;        1025 AA.
AC   Q9BYX4; Q2NKL6; Q6DC96; Q86X56; Q96MX8; Q9H3G6;
DT   12-APR-2005, integrated into UniProtKB/Swiss-Prot.
DT   20-MAR-2007, sequence version 3.
DT   24-JAN-2024, entry version 197.
DE   RecName: Full=Interferon-induced helicase C domain-containing protein 1 {ECO:0000305};
DE            EC=3.6.4.13 {ECO:0000269|PubMed:19211564, ECO:0000269|PubMed:22160685};
DE   AltName: Full=Clinically amyopathic dermatomyositis autoantigen 140 kDa;
DE            Short=CADM-140 autoantigen;
DE   AltName: Full=Helicase with 2 CARD domains;
DE            Short=Helicard;
DE   AltName: Full=Interferon-induced with helicase C domain protein 1;
DE   AltName: Full=Melanoma differentiation-associated protein 5;
DE            Short=MDA-5;
DE   AltName: Full=Murabutide down-regulated protein;
DE   AltName: Full=RIG-I-like receptor 2;
DE            Short=RLR-2;
DE   AltName: Full=RNA helicase-DEAD box protein 116;
GN   Name=IFIH1 {ECO:0000312|HGNC:HGNC:18873};
GN   Synonyms=MDA5 {ECO:0000303|PubMed:19211564, ECO:0000303|PubMed:33727702},
GN   RH116;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INDUCTION, SUBCELLULAR LOCATION,
RP   AND TISSUE SPECIFICITY.
RC   TISSUE=Melanoma;
RX   PubMed=11805321; DOI=10.1073/pnas.022637199;
RA   Kang D.-C., Gopalkrishnan R.V., Wu Q., Jankowsky E., Pyle A.M.,
RA   Fisher P.B.;
RT   "mda-5: an interferon-inducible putative RNA helicase with double-stranded
RT   RNA-dependent ATPase activity and melanoma growth-suppressive properties.";
RL   Proc. Natl. Acad. Sci. U.S.A. 99:637-642(2002).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, SUBCELLULAR LOCATION,
RP   TISSUE SPECIFICITY, AND VARIANT ARG-843.
RC   TISSUE=Spleen;
RX   PubMed=14645903; DOI=10.1099/vir.0.19300-0;
RA   Cocude C., Truong M.-J., Billaut-Mulot O., Delsart V., Darcissac E.,
RA   Capron A., Mouton Y., Bahr G.M.;
RT   "A novel cellular RNA helicase, RH116, differentially regulates cell
RT   growth, programmed cell death and human immunodeficiency virus type 1
RT   replication.";
RL   J. Gen. Virol. 84:3215-3225(2003).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANTS
RP   ARG-843 AND THR-946.
RC   TISSUE=Uterus;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 475-1025 (ISOFORM 1), AND VARIANTS ARG-843
RP   AND THR-946.
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [5]
RP   MUTAGENESIS OF ASP-251 AND GLU-444, AND TISSUE SPECIFICITY.
RX   PubMed=12015121; DOI=10.1016/s0960-9822(02)00842-4;
RA   Kovacsovics M., Martinon F., Micheau O., Bodmer J.-L., Hofmann K.,
RA   Tschopp J.;
RT   "Overexpression of Helicard, a CARD-containing helicase cleaved during
RT   apoptosis, accelerates DNA degradation.";
RL   Curr. Biol. 12:838-843(2002).
RN   [6]
RP   ERRATUM OF PUBMED:12015121.
RA   Kovacsovics M., Martinon F., Micheau O., Bodmer J.-L., Hofmann K.,
RA   Tschopp J.;
RL   Curr. Biol. 12:1633-1633(2002).
RN   [7]
RP   INTERACTION WITH PARAMYXOVIRUSES V PROTEIN (MICROBIAL INFECTION).
RX   PubMed=15563593; DOI=10.1073/pnas.0407639101;
RA   Andrejeva J., Childs K.S., Young D.F., Carlos T.S., Stock N., Goodbourn S.,
RA   Randall R.E.;
RT   "The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase,
RT   mda-5, and inhibit its activation of the IFN-beta promoter.";
RL   Proc. Natl. Acad. Sci. U.S.A. 101:17264-17269(2004).
RN   [8]
RP   INTERACTION WITH MAVS/IPS1.
RX   PubMed=16127453; DOI=10.1038/ni1243;
RA   Kawai T., Takahashi K., Sato S., Coban C., Kumar H., Kato H., Ishii K.J.,
RA   Takeuchi O., Akira S.;
RT   "IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon
RT   induction.";
RL   Nat. Immunol. 6:981-988(2005).
RN   [9]
RP   INTERACTION WITH MAVS/IPS1.
RX   PubMed=16177806; DOI=10.1038/nature04193;
RA   Meylan E., Curran J., Hofmann K., Moradpour D., Binder M.,
RA   Bartenschlager R., Tschopp J.;
RT   "Cardif is an adaptor protein in the RIG-I antiviral pathway and is
RT   targeted by hepatitis C virus.";
RL   Nature 437:1167-1172(2005).
RN   [10]
RP   UBIQUITINATION.
RX   PubMed=17460044; DOI=10.1073/pnas.0611551104;
RA   Arimoto K., Takahashi H., Hishiki T., Konishi H., Fujita T., Shimotohno K.;
RT   "Negative regulation of the RIG-I signaling by the ubiquitin ligase
RT   RNF125.";
RL   Proc. Natl. Acad. Sci. U.S.A. 104:7500-7505(2007).
RN   [11]
RP   INTERACTION WITH IKBKE; MAVS AND TKFC.
RX   PubMed=17600090; DOI=10.1073/pnas.0700544104;
RA   Diao F., Li S., Tian Y., Zhang M., Xu L.G., Zhang Y., Wang R.P., Chen D.,
RA   Zhai Z., Zhong B., Tien P., Shu H.B.;
RT   "Negative regulation of MDA5- but not RIG-I-mediated innate antiviral
RT   signaling by the dihydroxyacetone kinase.";
RL   Proc. Natl. Acad. Sci. U.S.A. 104:11706-11711(2007).
RN   [12]
RP   INTERACTION WITH ATG5 AND ATG12.
RX   PubMed=17709747; DOI=10.1073/pnas.0704014104;
RA   Jounai N., Takeshita F., Kobiyama K., Sawano A., Miyawaki A., Xin K.Q.,
RA   Ishii K.J., Kawai T., Akira S., Suzuki K., Okuda K.;
RT   "The Atg5-Atg12 conjugate associates with innate antiviral immune
RT   responses.";
RL   Proc. Natl. Acad. Sci. U.S.A. 104:14050-14055(2007).
RN   [13]
RP   INVOLVEMENT IN CLINICALLY AMYOPATHIC DERMATOMYOSITIS, AND IDENTIFICATION AS
RP   CADM-140 AUTOANTIGEN.
RX   PubMed=19565506; DOI=10.1002/art.24621;
RA   Sato S., Hoshino K., Satoh T., Fujita T., Kawakami Y., Fujita T.,
RA   Kuwana M.;
RT   "RNA helicase encoded by melanoma differentiation-associated gene 5 is a
RT   major autoantigen in patients with clinically amyopathic dermatomyositis:
RT   Association with rapidly progressive interstitial lung disease.";
RL   Arthritis Rheum. 60:2193-2200(2009).
RN   [14]
RP   FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF LYS-335; 443-ASP--HIS-446;
RP   488-THR--SER-490; 789-THR--GLU-793 AND 818-GLN--ARG-822.
RX   PubMed=19211564; DOI=10.1074/jbc.m807365200;
RA   Bamming D., Horvath C.M.;
RT   "Regulation of signal transduction by enzymatically inactive antiviral RNA
RT   helicase proteins MDA5, RIG-I, and LGP2.";
RL   J. Biol. Chem. 284:9700-9712(2009).
RN   [15]
RP   FUNCTION.
RX   PubMed=19656871; DOI=10.1128/jvi.00770-09;
RA   Pichlmair A., Schulz O., Tan C.P., Rehwinkel J., Kato H., Takeuchi O.,
RA   Akira S., Way M., Schiavo G., Reis e Sousa C.;
RT   "Activation of MDA5 requires higher-order RNA structures generated during
RT   virus infection.";
RL   J. Virol. 83:10761-10769(2009).
RN   [16]
RP   INTERACTION WITH PCBP2.
RX   PubMed=19881509; DOI=10.1038/ni.1815;
RA   You F., Sun H., Zhou X., Sun W., Liang S., Zhai Z., Jiang Z.;
RT   "PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin
RT   ligase AIP4.";
RL   Nat. Immunol. 10:1300-1308(2009).
RN   [17]
RP   INTERACTION WITH NLRC5.
RX   PubMed=20434986; DOI=10.1016/j.cell.2010.03.040;
RA   Cui J., Zhu L., Xia X., Wang H.Y., Legras X., Hong J., Ji J., Shen P.,
RA   Zheng S., Chen Z.J., Wang R.F.;
RT   "NLRC5 negatively regulates the NF-kappaB and type I interferon signaling
RT   pathways.";
RL   Cell 141:483-496(2010).
RN   [18]
RP   UBIQUITINATION, AND DEUBIQUITINATION BY USP17L2.
RX   PubMed=20368735; DOI=10.1038/cr.2010.41;
RA   Chen R., Zhang L., Zhong B., Tan B., Liu Y., Shu H.B.;
RT   "The ubiquitin-specific protease 17 is involved in virus-triggered type I
RT   IFN signaling.";
RL   Cell Res. 20:802-811(2010).
RN   [19]
RP   INTERACTION WITH DDX3X.
RX   PubMed=20127681; DOI=10.1002/eji.200940203;
RA   Oshiumi H., Sakai K., Matsumoto M., Seya T.;
RT   "DEAD/H BOX 3 (DDX3) helicase binds the RIG-I adaptor IPS-1 to up-regulate
RT   IFN-beta-inducing potential.";
RL   Eur. J. Immunol. 40:940-948(2010).
RN   [20]
RP   INVOLVEMENT IN CLINICALLY AMYOPATHIC DERMATOMYOSITIS, IDENTIFICATION AS
RP   CADM-140 AUTOANTIGEN, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX   PubMed=20015976; DOI=10.1093/rheumatology/kep375;
RA   Nakashima R., Imura Y., Kobayashi S., Yukawa N., Yoshifuji H., Nojima T.,
RA   Kawabata D., Ohmura K., Usui T., Fujii T., Okawa K., Mimori T.;
RT   "The RIG-I-like receptor IFIH1/MDA5 is a dermatomyositis-specific
RT   autoantigen identified by the anti-CADM-140 antibody.";
RL   Rheumatology 49:433-440(2010).
RN   [21]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA   Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA   Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT   "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT   site occupancy during mitosis.";
RL   Sci. Signal. 3:RA3-RA3(2010).
RN   [22]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [23]
RP   REVIEW ON FUNCTION.
RX   PubMed=21616437; DOI=10.1016/j.immuni.2011.05.003;
RA   Loo Y.M., Gale M. Jr.;
RT   "Immune signaling by RIG-I-like receptors.";
RL   Immunity 34:680-692(2011).
RN   [24]
RP   REVIEW ON FUNCTION.
RX   PubMed=21884169; DOI=10.1111/j.1600-065x.2011.01052.x;
RA   Kato H., Takahasi K., Fujita T.;
RT   "RIG-I-like receptors: cytoplasmic sensors for non-self RNA.";
RL   Immunol. Rev. 243:91-98(2011).
RN   [25]
RP   FUNCTION.
RX   PubMed=21742966; DOI=10.4049/jimmunol.1100361;
RA   Jiang M., Osterlund P., Sarin L.P., Poranen M.M., Bamford D.H., Guo D.,
RA   Julkunen I.;
RT   "Innate immune responses in human monocyte-derived dendritic cells are
RT   highly dependent on the size and the 5' phosphorylation of RNA molecules.";
RL   J. Immunol. 187:1713-1721(2011).
RN   [26]
RP   REVIEW ON FUNCTION.
RX   PubMed=20950133; DOI=10.1089/jir.2010.0057;
RA   Onoguchi K., Yoneyama M., Fujita T.;
RT   "Retinoic acid-inducible gene-I-like receptors.";
RL   J. Interferon Cytokine Res. 31:27-31(2011).
RN   [27]
RP   INTERACTION WITH DDX60.
RX   PubMed=21791617; DOI=10.1128/mcb.01368-10;
RA   Miyashita M., Oshiumi H., Matsumoto M., Seya T.;
RT   "DDX60, a DEXD/H box helicase, is a novel antiviral factor promoting RIG-I-
RT   like receptor-mediated signaling.";
RL   Mol. Cell. Biol. 31:3802-3819(2011).
RN   [28]
RP   SUMOYLATION, AND INTERACTION WITH PIAS2-BETA.
RX   PubMed=21156324; DOI=10.1016/j.molimm.2010.09.003;
RA   Fu J., Xiong Y., Xu Y., Cheng G., Tang H.;
RT   "MDA5 is SUMOylated by PIAS2? in the upregulation of type I interferon
RT   signaling.";
RL   Mol. Immunol. 48:415-422(2011).
RN   [29]
RP   REVIEW ON FUNCTION.
RX   PubMed=21245900; DOI=10.1038/ni0211-114;
RA   Garcia-Sastre A.;
RT   "2 methylate or not 2 methylate: viral evasion of the type I interferon
RT   response.";
RL   Nat. Immunol. 12:114-115(2011).
RN   [30]
RP   FUNCTION.
RX   PubMed=21217758; DOI=10.1038/ni.1979;
RA   Zuest R., Cervantes-Barragan L., Habjan M., Maier R., Neuman B.W.,
RA   Ziebuhr J., Szretter K.J., Baker S.C., Barchet W., Diamond M.S.,
RA   Siddell S.G., Ludewig B., Thiel V.;
RT   "Ribose 2'-O-methylation provides a molecular signature for the distinction
RT   of self and non-self mRNA dependent on the RNA sensor Mda5.";
RL   Nat. Immunol. 12:137-143(2011).
RN   [31]
RP   SUBUNIT, FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=22160685; DOI=10.1073/pnas.1113651108;
RA   Peisley A., Lin C., Wu B., Orme-Johnson M., Liu M., Walz T., Hur S.;
RT   "Cooperative assembly and dynamic disassembly of MDA5 filaments for viral
RT   dsRNA recognition.";
RL   Proc. Natl. Acad. Sci. U.S.A. 108:21010-21015(2011).
RN   [32]
RP   INTERACTION WITH HERPES SIMPLEX VIRUS 1 PROTEIN US11 (MICROBIAL INFECTION).
RX   PubMed=22301138; DOI=10.1128/jvi.06713-11;
RA   Xing J., Wang S., Lin R., Mossman K.L., Zheng C.;
RT   "Herpes simplex virus 1 tegument protein US11 downmodulates the RLR
RT   signaling pathway via direct interaction with RIG-I and MDA-5.";
RL   J. Virol. 86:3528-3540(2012).
RN   [33]
RP   INTERACTION WITH ANKRD17.
RX   PubMed=23711367; DOI=10.1016/j.febslet.2013.05.037;
RA   Menning M., Kufer T.A.;
RT   "A role for the Ankyrin repeat containing protein Ankrd17 in Nod1- and
RT   Nod2-mediated inflammatory responses.";
RL   FEBS Lett. 587:2137-2142(2013).
RN   [34]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA   Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT   phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [35]
RP   PROTEOLYTIC CLEAVAGE (MICROBIAL INFECTION).
RX   PubMed=24390337; DOI=10.1128/jvi.02712-13;
RA   Feng Q., Langereis M.A., Lork M., Nguyen M., Hato S.V., Lanke K., Emdad L.,
RA   Bhoopathi P., Fisher P.B., Lloyd R.E., van Kuppeveld F.J.;
RT   "Enterovirus 2Apro targets MDA5 and MAVS in infected cells.";
RL   J. Virol. 88:3369-3378(2014).
RN   [36]
RP   PHOSPHORYLATION AT SER-828, AND MUTAGENESIS OF SER-828 AND THR-829.
RX   PubMed=25865883; DOI=10.1016/j.celrep.2015.03.027;
RA   Takashima K., Oshiumi H., Takaki H., Matsumoto M., Seya T.;
RT   "RIOK3-mediated phosphorylation of MDA5 interferes with its assembly and
RT   attenuates the innate immune response.";
RL   Cell Rep. 11:192-200(2015).
RN   [37]
RP   INTERACTION WITH ECSIT.
RX   PubMed=25228397; DOI=10.1159/000365971;
RA   Lei C.Q., Zhang Y., Li M., Jiang L.Q., Zhong B., Kim Y.H., Shu H.B.;
RT   "ECSIT bridges RIG-I-like receptors to VISA in signaling events of innate
RT   antiviral responses.";
RL   J. Innate Immun. 7:153-164(2015).
RN   [38]
RP   INTERACTION WITH RNF123.
RX   PubMed=27312109; DOI=10.15252/embr.201541703;
RA   Wang S., Yang Y.K., Chen T., Zhang H., Yang W.W., Song S.S., Zhai Z.H.,
RA   Chen D.Y.;
RT   "RNF123 has an E3 ligase-independent function in RIG-I-like receptor-
RT   mediated antiviral signaling.";
RL   EMBO Rep. 17:1155-1168(2016).
RN   [39]
RP   INTERACTION WITH COXSACKIEVIRUS A16 PROTEASE 3C (MICROBIAL INFECTION), AND
RP   INTERACTION WITH HUMAN ENTEROVIRUS D68 PROTEASE 3C (MICROBIAL INFECTION).
RX   PubMed=28424289; DOI=10.1128/jvi.00546-17;
RA   Rui Y., Su J., Wang H., Chang J., Wang S., Zheng W., Cai Y., Wei W.,
RA   Gordy J.T., Markham R., Kong W., Zhang W., Yu X.F.;
RT   "Disruption of MDA5-Mediated Innate Immune Responses by the 3C Proteins of
RT   Coxsackievirus A16, Coxsackievirus A6, and Enterovirus D68.";
RL   J. Virol. 91:0-0(2017).
RN   [40]
RP   FUNCTION, AND UBIQUITINATION BY TRIM40.
RX   PubMed=29117565; DOI=10.1016/j.celrep.2017.10.020;
RA   Zhao C., Jia M., Song H., Yu Z., Wang W., Li Q., Zhang L., Zhao W., Cao X.;
RT   "The E3 Ubiquitin Ligase TRIM40 Attenuates Antiviral Immune Responses by
RT   Targeting MDA5 and RIG-I.";
RL   Cell Rep. 21:1613-1623(2017).
RN   [41]
RP   FUNCTION, AND UBIQUITINATION BY TRIM65.
RX   PubMed=28594402; DOI=10.1038/cddis.2017.257;
RA   Meng J., Yao Z., He Y., Zhang R., Zhang Y., Yao X., Yang H., Chen L.,
RA   Zhang Z., Zhang H., Bao X., Hu G., Wu T., Cheng J.;
RT   "ARRDC4 regulates enterovirus 71-induced innate immune response by
RT   promoting K63 polyubiquitination of MDA5 through TRIM65.";
RL   Cell Death Dis. 8:e2866-e2866(2017).
RN   [42]
RP   INTERACTION WITH ENCEPHALOMYOCARDITIS VIRUS PROTEIN 2C (MICROBIAL
RP   INFECTION).
RX   PubMed=30312637; DOI=10.1016/j.antiviral.2018.10.010;
RA   Li L., Fan H., Song Z., Liu X., Bai J., Jiang P.;
RT   "Encephalomyocarditis virus 2C protein antagonizes interferon-beta
RT   signaling pathway through interaction with MDA5.";
RL   Antiviral Res. 161:70-84(2018).
RN   [43]
RP   INTERACTION WITH ZCCHC3, AND UBIQUITINATION.
RX   PubMed=30193849; DOI=10.1016/j.immuni.2018.08.014;
RA   Lian H., Zang R., Wei J., Ye W., Hu M.M., Chen Y.D., Zhang X.N., Guo Y.,
RA   Lei C.Q., Yang Q., Luo W.W., Li S., Shu H.B.;
RT   "The zinc-finger protein ZCCHC3 binds RNA and facilitates viral RNA sensing
RT   and activation of the RIG-I-like receptors.";
RL   Immunity 49:438-448(2018).
RN   [44]
RP   FUNCTION, INTERACTION WITH IFIH1, AND SUBCELLULAR LOCATION.
RX   PubMed=32169843; DOI=10.4049/jimmunol.1900667;
RA   Wu X.M., Zhang J., Li P.W., Hu Y.W., Cao L., Ouyang S., Bi Y.H., Nie P.,
RA   Chang M.X.;
RT   "NOD1 Promotes Antiviral Signaling by Binding Viral RNA and Regulating the
RT   Interaction of MDA5 and MAVS.";
RL   J. Immunol. 204:2216-2231(2020).
RN   [45]
RP   FUNCTION.
RX   PubMed=33440148; DOI=10.1016/j.celrep.2020.108628;
RA   Yin X., Riva L., Pu Y., Martin-Sancho L., Kanamune J., Yamamoto Y.,
RA   Sakai K., Gotoh S., Miorin L., De Jesus P.D., Yang C.C., Herbert K.M.,
RA   Yoh S., Hultquist J.F., Garcia-Sastre A., Chanda S.K.;
RT   "MDA5 Governs the Innate Immune Response to SARS-CoV-2 in Lung Epithelial
RT   Cells.";
RL   Cell Rep. 34:108628-108628(2021).
RN   [46]
RP   FUNCTION.
RX   PubMed=33514628; DOI=10.1128/jvi.02415-20;
RA   Rebendenne A., Valadao A.L.C., Tauziet M., Maarifi G., Bonaventure B.,
RA   McKellar J., Planes R., Nisole S., Arnaud-Arnould M., Moncorge O.,
RA   Goujon C.;
RT   "SARS-CoV-2 triggers an MDA-5-dependent interferon response which is unable
RT   to control replication in lung epithelial cells.";
RL   J. Virol. 0:0-0(2021).
RN   [47]
RP   ISGYLATION AT LYS-23 AND LYS-43, INTERACTION WITH SARS-COV-2 VIRUS PROTEIN
RP   NSP3 (MICROBIAL INFECTION), FUNCTION, MUTAGENESIS OF LYS-23; LYS-43;
RP   LYS-68; 74-GLY-TRP-75; SER-88; 841-ILE-GLU-842 AND 848-ASP-PHE-849,
RP   SUBUNIT, PHOSPHORYLATION AT SER-88, AND SUBCELLULAR LOCATION.
RX   PubMed=33727702; DOI=10.1038/s41564-021-00884-1;
RA   Liu G., Lee J.H., Parker Z.M., Acharya D., Chiang J.J., van Gent M.,
RA   Riedl W., Davis-Gardner M.E., Wies E., Chiang C., Gack M.U.;
RT   "ISG15-dependent activation of the sensor MDA5 is antagonized by the SARS-
RT   CoV-2 papain-like protease to evade host innate immunity.";
RL   Nat. Microbiol. 6:467-478(2021).
RN   [48]
RP   X-RAY CRYSTALLOGRAPHY (1.45 ANGSTROMS) OF 893-1017 IN COMPLEX WITH ZINC
RP   IONS.
RX   PubMed=19531363; DOI=10.1016/j.abb.2009.06.008;
RA   Li X., Lu C., Stewart M., Xu H., Strong R.K., Igumenova T., Li P.;
RT   "Structural basis of double-stranded RNA recognition by the RIG-I like
RT   receptor MDA5.";
RL   Arch. Biochem. Biophys. 488:23-33(2009).
RN   [49]
RP   STRUCTURE BY NMR OF 896-1025 IN COMPLEX WITH ZINC IONS.
RX   PubMed=19380577; DOI=10.1074/jbc.m109.007179;
RA   Takahasi K., Kumeta H., Tsuduki N., Narita R., Shigemoto T., Hirai R.,
RA   Yoneyama M., Horiuchi M., Ogura K., Fujita T., Inagaki F.;
RT   "Solution structures of cytosolic RNA sensor MDA5 and LGP2 C-terminal
RT   domains: identification of the RNA recognition loop in RIG-I-like
RT   receptors.";
RL   J. Biol. Chem. 284:17465-17474(2009).
RN   [50]
RP   X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 277-490.
RG   Structural genomics consortium (SGC);
RT   "Human dech-box RNA helicase mda5 (melanoma differentiation-associated
RT   protein 5), dech-domain.";
RL   Submitted (FEB-2009) to the PDB data bank.
RN   [51]
RP   VARIANT THR-946, AND POSSIBLE ASSOCIATION WITH T1D19.
RX   PubMed=16699517; DOI=10.1038/ng1800;
RA   Smyth D.J., Cooper J.D., Bailey R., Field S., Burren O., Smink L.J.,
RA   Guja C., Ionescu-Tirgoviste C., Widmer B., Dunger D.B., Savage D.A.,
RA   Walker N.M., Clayton D.G., Todd J.A.;
RT   "A genome-wide association study of nonsynonymous SNPs identifies a type 1
RT   diabetes locus in the interferon-induced helicase (IFIH1) region.";
RL   Nat. Genet. 38:617-619(2006).
RN   [52]
RP   INVOLVEMENT IN AGS7, VARIANTS AGS7 PHE-372; THR-452 AND HIS-779, AND
RP   CHARACTERIZATION OF VARIANTS AGS7 PHE-372; THR-452 AND HIS-779.
RX   PubMed=24995871; DOI=10.1016/j.ajhg.2014.06.007;
RA   Oda H., Nakagawa K., Abe J., Awaya T., Funabiki M., Hijikata A.,
RA   Nishikomori R., Funatsuka M., Ohshima Y., Sugawara Y., Yasumi T., Kato H.,
RA   Shirai T., Ohara O., Fujita T., Heike T.;
RT   "Aicardi-Goutieres syndrome is caused by IFIH1 mutations.";
RL   Am. J. Hum. Genet. 95:121-125(2014).
RN   [53]
RP   INVOLVEMENT IN AGS7, VARIANTS AGS7 GLY-337; VAL-393; ARG-495; GLN-720;
RP   HIS-779 AND CYS-779, AND CHARACTERIZATION OF VARIANTS AGS7 GLY-337;
RP   VAL-393; ARG-495; GLN-720; HIS-779 AND CYS-779.
RX   PubMed=24686847; DOI=10.1038/ng.2933;
RA   Rice G.I., del Toro Duany Y., Jenkinson E.M., Forte G.M., Anderson B.H.,
RA   Ariaudo G., Bader-Meunier B., Baildam E.M., Battini R., Beresford M.W.,
RA   Casarano M., Chouchane M., Cimaz R., Collins A.E., Cordeiro N.J.,
RA   Dale R.C., Davidson J.E., De Waele L., Desguerre I., Faivre L., Fazzi E.,
RA   Isidor B., Lagae L., Latchman A.R., Lebon P., Li C., Livingston J.H.,
RA   Lourenco C.M., Mancardi M.M., Masurel-Paulet A., McInnes I.B.,
RA   Menezes M.P., Mignot C., O'Sullivan J., Orcesi S., Picco P.P., Riva E.,
RA   Robinson R.A., Rodriguez D., Salvatici E., Scott C., Szybowska M.,
RA   Tolmie J.L., Vanderver A., Vanhulle C., Vieira J.P., Webb K., Whitney R.N.,
RA   Williams S.G., Wolfe L.A., Zuberi S.M., Hur S., Crow Y.J.;
RT   "Gain-of-function mutations in IFIH1 cause a spectrum of human disease
RT   phenotypes associated with upregulated type I interferon signaling.";
RL   Nat. Genet. 46:503-509(2014).
RN   [54]
RP   INVOLVEMENT IN SGMRT1, VARIANT SGMRT1 GLN-822, AND CHARACTERIZATION OF
RP   VARIANT SGMRT1 GLN-822.
RX   PubMed=25620204; DOI=10.1016/j.ajhg.2014.12.014;
RA   Rutsch F., MacDougall M., Lu C., Buers I., Mamaeva O., Nitschke Y.,
RA   Rice G.I., Erlandsen H., Kehl H.G., Thiele H., Nurnberg P., Hohne W.,
RA   Crow Y.J., Feigenbaum A., Hennekam R.C.;
RT   "A specific IFIH1 gain-of-function mutation causes Singleton-Merten
RT   syndrome.";
RL   Am. J. Hum. Genet. 96:275-282(2015).
RN   [55]
RP   VARIANT IMD95 GLU-365, CHARACTERIZATION OF VARIANT IMD95 GLU-365, FUNCTION,
RP   AND INVOLVEMENT IN IMD95.
RX   PubMed=28606988; DOI=10.1084/jem.20161759;
RA   Lamborn I.T., Jing H., Zhang Y., Drutman S.B., Abbott J.K., Munir S.,
RA   Bade S., Murdock H.M., Santos C.P., Brock L.G., Masutani E., Fordjour E.Y.,
RA   McElwee J.J., Hughes J.D., Nichols D.P., Belkadi A., Oler A.J.,
RA   Happel C.S., Matthews H.F., Abel L., Collins P.L., Subbarao K.,
RA   Gelfand E.W., Ciancanelli M.J., Casanova J.L., Su H.C.;
RT   "Recurrent rhinovirus infections in a child with inherited MDA5
RT   deficiency.";
RL   J. Exp. Med. 214:1949-1972(2017).
RN   [56]
RP   VARIANT IMD95 889-LYS--ASP-1025 DEL, AND CHARACTERIZATION OF VARIANT IMD95
RP   889-LYS--ASP-1025 DEL.
RX   PubMed=29018476; DOI=10.3389/fgene.2017.00130;
RA   Zaki M., Thoenes M., Kawalia A., Nuernberg P., Kaiser R., Heller R.,
RA   Bolz H.J.;
RT   "Recurrent and prolonged infections in a child with a homozygous IFIH1
RT   nonsense mutation.";
RL   Front. Genet. 8:130-130(2017).
CC   -!- FUNCTION: Innate immune receptor which acts as a cytoplasmic sensor of
CC       viral nucleic acids and plays a major role in sensing viral infection
CC       and in the activation of a cascade of antiviral responses including the
CC       induction of type I interferons and pro-inflammatory cytokines
CC       (PubMed:32169843, PubMed:33727702, PubMed:28594402). Its ligands
CC       include mRNA lacking 2'-O-methylation at their 5' cap and long-dsRNA
CC       (>1 kb in length) (PubMed:22160685). Upon ligand binding it associates
CC       with mitochondria antiviral signaling protein (MAVS/IPS1) which
CC       activates the IKK-related kinases: TBK1 and IKBKE which phosphorylate
CC       interferon regulatory factors: IRF3 and IRF7 which in turn activate
CC       transcription of antiviral immunological genes, including interferons
CC       (IFNs); IFN-alpha and IFN-beta. Responsible for detecting the
CC       Picornaviridae family members such as encephalomyocarditis virus
CC       (EMCV), mengo encephalomyocarditis virus (ENMG), and rhinovirus
CC       (PubMed:28606988). Detects coronavirus SARS-CoV-2 (PubMed:33440148,
CC       PubMed:33514628). Can also detect other viruses such as dengue virus
CC       (DENV), west Nile virus (WNV), and reovirus. Also involved in antiviral
CC       signaling in response to viruses containing a dsDNA genome, such as
CC       vaccinia virus. Plays an important role in amplifying innate immune
CC       signaling through recognition of RNA metabolites that are produced
CC       during virus infection by ribonuclease L (RNase L). May play an
CC       important role in enhancing natural killer cell function and may be
CC       involved in growth inhibition and apoptosis in several tumor cell
CC       lines. {ECO:0000269|PubMed:14645903, ECO:0000269|PubMed:19211564,
CC       ECO:0000269|PubMed:19656871, ECO:0000269|PubMed:21217758,
CC       ECO:0000269|PubMed:21742966, ECO:0000269|PubMed:22160685,
CC       ECO:0000269|PubMed:28594402, ECO:0000269|PubMed:28606988,
CC       ECO:0000269|PubMed:29117565, ECO:0000269|PubMed:33440148,
CC       ECO:0000269|PubMed:33514628, ECO:0000269|PubMed:33727702}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=ATP + H2O = ADP + H(+) + phosphate; Xref=Rhea:RHEA:13065,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=3.6.4.13;
CC         Evidence={ECO:0000269|PubMed:19211564, ECO:0000269|PubMed:22160685};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:13066;
CC         Evidence={ECO:0000305|PubMed:19211564, ECO:0000305|PubMed:22160685};
CC   -!- SUBUNIT: Monomer in the absence of ligands and homodimerizes in the
CC       presence of dsRNA ligands. Can assemble into helical or linear
CC       polymeric filaments on long dsRNA (PubMed:33727702). Interacts with
CC       MAVS/IPS1. Interacts (via the CARD domains) with TKFC, the interaction
CC       is inhibited by viral infection (PubMed:17600090). Interacts with
CC       PCBP2. Interacts with NLRC5. Interacts with PIAS2-beta. Interacts with
CC       DDX60. Interacts with ANKRD17. Interacts with IKBKE (PubMed:17600090).
CC       Interacts with ATG5 and ATG12, either as ATG5 and ATG12 monomers or as
CC       ATG12-ATG5 conjugates (PubMed:17709747). Interacts with ZCCHC3; leading
CC       to activate IFIH1/MDA5 (PubMed:30193849). Interacts with RNF123
CC       (PubMed:27312109). Interacts with DDX3X (PubMed:20127681). Interacts
CC       with NOD1; this interaction promotes transcription of antiviral genes
CC       and inhibition of viral replication (PubMed:32169843). Interacts with
CC       ECSIT; this interaction bridges IFIH1 to the MAVS complex at the
CC       mitochondrion (PubMed:25228397). {ECO:0000269|PubMed:15563593,
CC       ECO:0000269|PubMed:16127453, ECO:0000269|PubMed:16177806,
CC       ECO:0000269|PubMed:17600090, ECO:0000269|PubMed:17709747,
CC       ECO:0000269|PubMed:19380577, ECO:0000269|PubMed:19531363,
CC       ECO:0000269|PubMed:19881509, ECO:0000269|PubMed:20127681,
CC       ECO:0000269|PubMed:20434986, ECO:0000269|PubMed:21156324,
CC       ECO:0000269|PubMed:21791617, ECO:0000269|PubMed:22160685,
CC       ECO:0000269|PubMed:23711367, ECO:0000269|PubMed:27312109,
CC       ECO:0000269|PubMed:30193849, ECO:0000269|PubMed:33727702}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with V protein of
CC       paramyxoviruses; these interactions prevent IFN-beta induction, and
CC       subsequent establishment of an antiviral state.
CC       {ECO:0000269|PubMed:15563593}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with herpes simplex virus 1
CC       protein US11; this interaction prevents the interaction of MAVS/IPS1 to
CC       IFIH1. {ECO:0000269|PubMed:22301138}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with Encephalomyocarditis
CC       virus protein 2C; this interaction inhibits the induction of the IFN-
CC       beta signal pathway. {ECO:0000269|PubMed:30312637}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with protease 3C of
CC       coxsackievirus A16; this interaction inhibits IFIH1 thereby attenuating
CC       type-I IFN production. {ECO:0000269|PubMed:28424289}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with SARS-COV-2 virus protein
CC       NSP3; the interaction antagonizes ISG15-dependent IFIH1 activation via
CC       active de-ISGylation. {ECO:0000269|PubMed:33727702}.
CC   -!- INTERACTION:
CC       Q9BYX4; Q9BYX4: IFIH1; NbExp=6; IntAct=EBI-6115771, EBI-6115771;
CC       Q9BYX4; Q14164: IKBKE; NbExp=2; IntAct=EBI-6115771, EBI-307369;
CC       Q9BYX4; P05161: ISG15; NbExp=7; IntAct=EBI-6115771, EBI-746466;
CC       Q9BYX4; Q14145: KEAP1; NbExp=3; IntAct=EBI-6115771, EBI-751001;
CC       Q9BYX4; Q7Z434: MAVS; NbExp=7; IntAct=EBI-6115771, EBI-995373;
CC       Q9BYX4; Q7Z434-1: MAVS; NbExp=3; IntAct=EBI-6115771, EBI-15577799;
CC       Q9BYX4; O75569: PRKRA; NbExp=4; IntAct=EBI-6115771, EBI-713955;
CC       Q9BYX4; O14730: RIOK3; NbExp=6; IntAct=EBI-6115771, EBI-1047061;
CC       Q9BYX4; Q96EQ8: RNF125; NbExp=2; IntAct=EBI-6115771, EBI-2339208;
CC       Q9BYX4; Q3LXA3: TKFC; NbExp=5; IntAct=EBI-6115771, EBI-4291069;
CC       Q9BYX4; P0DTC5: M; Xeno; NbExp=3; IntAct=EBI-6115771, EBI-25475853;
CC       Q9BYX4; P0C774: P/V; Xeno; NbExp=3; IntAct=EBI-6115771, EBI-3650423;
CC       Q9BYX4; P11207: P/V; Xeno; NbExp=3; IntAct=EBI-6115771, EBI-6148694;
CC       Q9BYX4; P30927: P/V; Xeno; NbExp=2; IntAct=EBI-6115771, EBI-6599165;
CC       Q9BYX4; Q9EMA9: P/V; Xeno; NbExp=2; IntAct=EBI-6115771, EBI-6598728;
CC       Q9BYX4; PRO_0000449621 [P0DTD1]: rep; Xeno; NbExp=2; IntAct=EBI-6115771, EBI-25492388;
CC       Q9BYX4; P04487: US11; Xeno; NbExp=4; IntAct=EBI-6115771, EBI-6150681;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:11805321,
CC       ECO:0000269|PubMed:14645903, ECO:0000269|PubMed:32169843,
CC       ECO:0000269|PubMed:33727702}. Nucleus {ECO:0000305}. Mitochondrion
CC       {ECO:0000269|PubMed:33727702}. Note=Upon viral RNA stimulation and
CC       ISGylation, translocates from cytosol to mitochondrion. May be found in
CC       the nucleus, during apoptosis.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q9BYX4-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q9BYX4-2; Sequence=VSP_013337, VSP_013338;
CC   -!- TISSUE SPECIFICITY: Widely expressed, at a low level. Expression is
CC       detected at slightly highest levels in placenta, pancreas and spleen
CC       and at barely levels in detectable brain, testis and lung.
CC       {ECO:0000269|PubMed:11805321, ECO:0000269|PubMed:12015121,
CC       ECO:0000269|PubMed:14645903}.
CC   -!- INDUCTION: By interferon (IFN) and TNF. {ECO:0000269|PubMed:11805321}.
CC   -!- PTM: Sumoylated. Sumoylation positively regulates its role in type I
CC       interferon induction and is enhanced by PIAS2-beta.
CC       {ECO:0000269|PubMed:21156324}.
CC   -!- PTM: Ubiquitinated by RNF125, leading to its degradation by the
CC       proteasome (PubMed:17460044). USP17/UPS17L2-dependent deubiquitination
CC       positively regulates the receptor (PubMed:20368735). Ubiquitinated by
CC       TRIM25 via 'Lys-63'-linked ubiquitination, promoting activation of
CC       IFIH1/MDA5 (PubMed:30193849). Ubiquitinated by TRIM40 via 'Lys-48'-
CC       linked ubiquitination; leading to proteasomal degradation
CC       (PubMed:29117565). Ubiquitinated by TRIM65 via 'Lys-63'-linked
CC       ubiquitination, promoting activation of IFIH1/MDA5 (PubMed:28594402).
CC       {ECO:0000269|PubMed:17460044, ECO:0000269|PubMed:20368735,
CC       ECO:0000269|PubMed:28594402, ECO:0000269|PubMed:29117565,
CC       ECO:0000269|PubMed:30193849}.
CC   -!- PTM: ISGylated by ISG15. ISGylation increases upon infection with
CC       dengue (DENV) or Zika (ZIKV) viruses. ISGylation at Lys-23 and Lys-43
CC       is dependent of dephosphorylation at Ser-88, regulates mitochondrial
CC       translocation and oligomerization. Essential for IFIH1/MDA5-mediated
CC       cytokine responses and restriction of virus replication.
CC       {ECO:0000269|PubMed:33727702}.
CC   -!- PTM: Phosphorylated at Ser-88. Dephosphorylated by phsophatases PP1;
CC       dephosphorylation precedes and is required for ISGylation.
CC       {ECO:0000269|PubMed:33727702}.
CC   -!- PTM: During apoptosis, processed into 3 cleavage products. The
CC       helicase-containing fragment, once liberated from the CARD domains,
CC       translocate from the cytoplasm to the nucleus. The processed protein
CC       significantly sensitizes cells to DNA degradation.
CC       {ECO:0000250|UniProtKB:Q8R5F7}.
CC   -!- PTM: (Microbial infection) Cleaved and inactivated by the protease 2A
CC       of coxsackievirus B3, poliovirus and enterovirus 71 allowing the virus
CC       to disrupt the host type I interferon production.
CC       {ECO:0000269|PubMed:24390337}.
CC   -!- DISEASE: Type 1 diabetes mellitus 19 (T1D19) [MIM:610155]: A
CC       multifactorial disorder of glucose homeostasis that is characterized by
CC       susceptibility to ketoacidosis in the absence of insulin therapy.
CC       Clinical features are polydipsia, polyphagia and polyuria which result
CC       from hyperglycemia-induced osmotic diuresis and secondary thirst. These
CC       derangements result in long-term complications that affect the eyes,
CC       kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:16699517}.
CC       Note=Disease susceptibility may be associated with variants affecting
CC       the gene represented in this entry.
CC   -!- DISEASE: Note=IFIH1 is the CADM-140 autoantigen, involved in clinically
CC       amyopathic dermatomyositis (CADM). This is a chronic inflammatory
CC       disorder that shows typical skin manifestations of dermatomyositis but
CC       has no or little evidence of clinical myositis. Anti-CADM-140
CC       antibodies appear to be specific to dermatomyositis, especially CADM.
CC       Patients with anti-CADM-140 antibodies frequently develop life-
CC       threatening acute progressive interstitial lung disease (ILD).
CC       {ECO:0000269|PubMed:19565506, ECO:0000269|PubMed:20015976}.
CC   -!- DISEASE: Aicardi-Goutieres syndrome 7 (AGS7) [MIM:615846]: A form of
CC       Aicardi-Goutieres syndrome, a genetically heterogeneous disease
CC       characterized by cerebral atrophy, leukoencephalopathy, intracranial
CC       calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis,
CC       increased CSF alpha-interferon, and negative serologic investigations
CC       for common prenatal infection. Clinical features as thrombocytopenia,
CC       hepatosplenomegaly and elevated hepatic transaminases along with
CC       intermittent fever may erroneously suggest an infective process. Severe
CC       neurological dysfunctions manifest in infancy as progressive
CC       microcephaly, spasticity, dystonic posturing and profound psychomotor
CC       retardation. Death often occurs in early childhood.
CC       {ECO:0000269|PubMed:24686847, ECO:0000269|PubMed:24995871}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- DISEASE: Singleton-Merten syndrome 1 (SGMRT1) [MIM:182250]: An
CC       autosomal dominant disorder with variable expression. Core features are
CC       marked aortic calcification, dental anomalies, osteopenia, acro-
CC       osteolysis, and to a lesser extent glaucoma, psoriasis, muscle
CC       weakness, and joint laxity. Dental anomalies include delayed eruption
CC       and immature root formation of anterior permanent teeth, early loss of
CC       permanent teeth due to short roots, acute root resorption, high caries,
CC       and aggressive alveolar bone loss. Additional clinical manifestations
CC       include particular facial characteristics and abnormal joint and muscle
CC       ligaments. {ECO:0000269|PubMed:25620204}. Note=The disease is caused by
CC       variants affecting the gene represented in this entry.
CC   -!- DISEASE: Immunodeficiency 95 (IMD95) [MIM:619773]: An autosomal
CC       recessive disorder characterized by the onset of recurrent and severe
CC       viral respiratory infections in infancy or early childhood, and
CC       impaired interferon production during viral infection.
CC       {ECO:0000269|PubMed:28606988, ECO:0000269|PubMed:29018476}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- MISCELLANEOUS: In HIV-1 infected HeLa-CD4 cells, overexpression of
CC       IFIH1 results in a great increase in the level of secreted viral p24
CC       protein.
CC   -!- SIMILARITY: Belongs to the helicase family. RLR subfamily.
CC       {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAH78180.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305};
CC       Sequence=BAB71141.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR   EMBL; AF095844; AAG34368.1; -; mRNA.
DR   EMBL; AY017378; AAG54076.1; -; mRNA.
DR   EMBL; BC046208; AAH46208.1; -; mRNA.
DR   EMBL; BC078180; AAH78180.1; ALT_SEQ; mRNA.
DR   EMBL; BC111750; AAI11751.1; -; mRNA.
DR   EMBL; AK056293; BAB71141.1; ALT_INIT; mRNA.
DR   CCDS; CCDS2217.1; -. [Q9BYX4-1]
DR   RefSeq; NP_071451.2; NM_022168.3. [Q9BYX4-1]
DR   PDB; 2RQB; NMR; -; A=896-1025.
DR   PDB; 3B6E; X-ray; 1.60 A; A=277-490.
DR   PDB; 3GA3; X-ray; 1.45 A; A=893-1017.
DR   PDB; 4GL2; X-ray; 3.56 A; A/B=306-1017.
DR   PDB; 7DNI; EM; 3.20 A; A/B/C/D=1-208.
DR   PDB; 7DNJ; EM; 3.30 A; A/B/C/D=1-208.
DR   PDB; 7JL0; EM; 4.30 A; A=287-1025.
DR   PDB; 7JL2; EM; 4.30 A; A/C/E=287-1025.
DR   PDBsum; 2RQB; -.
DR   PDBsum; 3B6E; -.
DR   PDBsum; 3GA3; -.
DR   PDBsum; 4GL2; -.
DR   PDBsum; 7DNI; -.
DR   PDBsum; 7DNJ; -.
DR   PDBsum; 7JL0; -.
DR   PDBsum; 7JL2; -.
DR   AlphaFoldDB; Q9BYX4; -.
DR   EMDB; EMD-22368; -.
DR   EMDB; EMD-22370; -.
DR   EMDB; EMD-30784; -.
DR   EMDB; EMD-30785; -.
DR   SMR; Q9BYX4; -.
DR   BioGRID; 122082; 44.
DR   DIP; DIP-42607N; -.
DR   IntAct; Q9BYX4; 58.
DR   STRING; 9606.ENSP00000497271; -.
DR   ChEMBL; CHEMBL4739862; -.
DR   iPTMnet; Q9BYX4; -.
DR   PhosphoSitePlus; Q9BYX4; -.
DR   BioMuta; IFIH1; -.
DR   DMDM; 134047802; -.
DR   EPD; Q9BYX4; -.
DR   jPOST; Q9BYX4; -.
DR   MassIVE; Q9BYX4; -.
DR   MaxQB; Q9BYX4; -.
DR   PaxDb; 9606-ENSP00000263642; -.
DR   PeptideAtlas; Q9BYX4; -.
DR   ProteomicsDB; 79740; -. [Q9BYX4-1]
DR   ProteomicsDB; 79741; -. [Q9BYX4-2]
DR   Pumba; Q9BYX4; -.
DR   Antibodypedia; 805; 566 antibodies from 42 providers.
DR   DNASU; 64135; -.
DR   Ensembl; ENST00000421365.2; ENSP00000408450.2; ENSG00000115267.10. [Q9BYX4-2]
DR   Ensembl; ENST00000649979.2; ENSP00000497271.1; ENSG00000115267.10. [Q9BYX4-1]
DR   GeneID; 64135; -.
DR   KEGG; hsa:64135; -.
DR   MANE-Select; ENST00000649979.2; ENSP00000497271.1; NM_022168.4; NP_071451.2.
DR   UCSC; uc002uce.5; human. [Q9BYX4-1]
DR   AGR; HGNC:18873; -.
DR   CTD; 64135; -.
DR   DisGeNET; 64135; -.
DR   GeneCards; IFIH1; -.
DR   GeneReviews; IFIH1; -.
DR   HGNC; HGNC:18873; IFIH1.
DR   HPA; ENSG00000115267; Tissue enhanced (bone).
DR   MalaCards; IFIH1; -.
DR   MIM; 182250; phenotype.
DR   MIM; 606951; gene.
DR   MIM; 610155; phenotype.
DR   MIM; 615846; phenotype.
DR   MIM; 619773; phenotype.
DR   neXtProt; NX_Q9BYX4; -.
DR   OpenTargets; ENSG00000115267; -.
DR   Orphanet; 51; Aicardi-Goutieres syndrome.
DR   Orphanet; 85191; Singleton-Merten dysplasia.
DR   PharmGKB; PA134889215; -.
DR   VEuPathDB; HostDB:ENSG00000115267; -.
DR   eggNOG; KOG0354; Eukaryota.
DR   GeneTree; ENSGT00940000153173; -.
DR   HOGENOM; CLU_006888_0_0_1; -.
DR   InParanoid; Q9BYX4; -.
DR   OMA; TFCQMNP; -.
DR   OrthoDB; 342391at2759; -.
DR   PhylomeDB; Q9BYX4; -.
DR   TreeFam; TF330258; -.
DR   PathwayCommons; Q9BYX4; -.
DR   Reactome; R-HSA-168928; DDX58/IFIH1-mediated induction of interferon-alpha/beta.
DR   Reactome; R-HSA-5689880; Ub-specific processing proteases.
DR   Reactome; R-HSA-5689896; Ovarian tumor domain proteases.
DR   Reactome; R-HSA-918233; TRAF3-dependent IRF activation pathway.
DR   Reactome; R-HSA-933541; TRAF6 mediated IRF7 activation.
DR   Reactome; R-HSA-933542; TRAF6 mediated NF-kB activation.
DR   Reactome; R-HSA-933543; NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10.
DR   Reactome; R-HSA-936440; Negative regulators of DDX58/IFIH1 signaling.
DR   Reactome; R-HSA-9692916; SARS-CoV-1 activates/modulates innate immune responses.
DR   Reactome; R-HSA-9705671; SARS-CoV-2 activates/modulates innate and adaptive immune responses.
DR   SignaLink; Q9BYX4; -.
DR   SIGNOR; Q9BYX4; -.
DR   BioGRID-ORCS; 64135; 9 hits in 1158 CRISPR screens.
DR   ChiTaRS; IFIH1; human.
DR   EvolutionaryTrace; Q9BYX4; -.
DR   GeneWiki; MDA5; -.
DR   GenomeRNAi; 64135; -.
DR   Pharos; Q9BYX4; Tbio.
DR   PRO; PR:Q9BYX4; -.
DR   Proteomes; UP000005640; Chromosome 2.
DR   RNAct; Q9BYX4; Protein.
DR   Bgee; ENSG00000115267; Expressed in palpebral conjunctiva and 195 other cell types or tissues.
DR   ExpressionAtlas; Q9BYX4; baseline and differential.
DR   Genevisible; Q9BYX4; HS.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005829; C:cytosol; TAS:Reactome.
DR   GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR   GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR   GO; GO:0032559; F:adenyl ribonucleotide binding; IDA:UniProt.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0016887; F:ATP hydrolysis activity; IMP:UniProtKB.
DR   GO; GO:0003677; F:DNA binding; IEA:InterPro.
DR   GO; GO:0003725; F:double-stranded RNA binding; IDA:UniProtKB.
DR   GO; GO:0042802; F:identical protein binding; IDA:UniProtKB.
DR   GO; GO:0038187; F:pattern recognition receptor activity; IDA:UniProt.
DR   GO; GO:0035639; F:purine ribonucleoside triphosphate binding; IDA:UniProt.
DR   GO; GO:0043021; F:ribonucleoprotein complex binding; IPI:UniProtKB.
DR   GO; GO:0003723; F:RNA binding; IDA:UniProtKB.
DR   GO; GO:0003724; F:RNA helicase activity; IMP:UniProtKB.
DR   GO; GO:0003727; F:single-stranded RNA binding; IDA:UniProtKB.
DR   GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR   GO; GO:0140374; P:antiviral innate immune response; IBA:GO_Central.
DR   GO; GO:0071360; P:cellular response to exogenous dsRNA; IMP:UniProtKB.
DR   GO; GO:0098586; P:cellular response to virus; IEP:ARUK-UCL.
DR   GO; GO:0002753; P:cytoplasmic pattern recognition receptor signaling pathway; TAS:UniProtKB.
DR   GO; GO:0051607; P:defense response to virus; IDA:UniProtKB.
DR   GO; GO:0009597; P:detection of virus; TAS:BHF-UCL.
DR   GO; GO:0045087; P:innate immune response; TAS:UniProtKB.
DR   GO; GO:0039530; P:MDA-5 signaling pathway; IDA:UniProtKB.
DR   GO; GO:0045071; P:negative regulation of viral genome replication; IDA:UniProtKB.
DR   GO; GO:0032727; P:positive regulation of interferon-alpha production; IMP:UniProtKB.
DR   GO; GO:0032728; P:positive regulation of interferon-beta production; IDA:UniProtKB.
DR   GO; GO:0032755; P:positive regulation of interleukin-6 production; IMP:UniProtKB.
DR   GO; GO:0060760; P:positive regulation of response to cytokine stimulus; IMP:UniProtKB.
DR   GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IMP:UniProtKB.
DR   GO; GO:0051259; P:protein complex oligomerization; IEA:Ensembl.
DR   GO; GO:0016925; P:protein sumoylation; IDA:UniProtKB.
DR   GO; GO:0034344; P:regulation of type III interferon production; TAS:UniProtKB.
DR   GO; GO:0009615; P:response to virus; IDA:UniProtKB.
DR   GO; GO:0060337; P:type I interferon-mediated signaling pathway; IEA:Ensembl.
DR   CDD; cd08818; CARD_MDA5_r1; 1.
DR   CDD; cd08819; CARD_MDA5_r2; 1.
DR   CDD; cd18074; DEXHc_RLR-2; 1.
DR   CDD; cd15807; MDA5_C; 1.
DR   CDD; cd12090; MDA5_ID; 1.
DR   CDD; cd18802; SF2_C_dicer; 1.
DR   Gene3D; 1.20.1320.30; -; 1.
DR   Gene3D; 1.10.533.10; Death Domain, Fas; 2.
DR   Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 2.
DR   Gene3D; 2.170.150.30; RIG-I-like receptor, C-terminal regulatory domain; 1.
DR   InterPro; IPR031964; CARD_dom.
DR   InterPro; IPR011029; DEATH-like_dom_sf.
DR   InterPro; IPR006935; Helicase/UvrB_N.
DR   InterPro; IPR014001; Helicase_ATP-bd.
DR   InterPro; IPR001650; Helicase_C.
DR   InterPro; IPR027417; P-loop_NTPase.
DR   InterPro; IPR041204; RIG-I-like_C.
DR   InterPro; IPR038557; RLR_C_sf.
DR   InterPro; IPR021673; RLR_CTR.
DR   PANTHER; PTHR14074; HELICASE WITH DEATH DOMAIN-RELATED; 1.
DR   PANTHER; PTHR14074:SF14; INTERFERON-INDUCED HELICASE C DOMAIN-CONTAINING PROTEIN 1; 1.
DR   Pfam; PF16739; CARD_2; 2.
DR   Pfam; PF00271; Helicase_C; 1.
DR   Pfam; PF04851; ResIII; 1.
DR   Pfam; PF18119; RIG-I_C; 1.
DR   Pfam; PF11648; RIG-I_C-RD; 1.
DR   SMART; SM00487; DEXDc; 1.
DR   SMART; SM00490; HELICc; 1.
DR   SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 2.
DR   PROSITE; PS51192; HELICASE_ATP_BIND_1; 1.
DR   PROSITE; PS51194; HELICASE_CTER; 1.
DR   PROSITE; PS51789; RLR_CTR; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Aicardi-Goutieres syndrome; Alternative splicing;
KW   Antiviral defense; ATP-binding; Cytoplasm; Diabetes mellitus;
KW   Disease variant; Helicase; Host-virus interaction; Hydrolase; Immunity;
KW   Innate immunity; Isopeptide bond; Metal-binding; Mitochondrion;
KW   Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome; Repeat;
KW   RNA-binding; Ubl conjugation; Zinc.
FT   CHAIN           1..1025
FT                   /note="Interferon-induced helicase C domain-containing
FT                   protein 1"
FT                   /id="PRO_0000102012"
FT   DOMAIN          7..97
FT                   /note="CARD 1"
FT   DOMAIN          110..190
FT                   /note="CARD 2"
FT   DOMAIN          316..509
FT                   /note="Helicase ATP-binding"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00541"
FT   DOMAIN          700..882
FT                   /note="Helicase C-terminal"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00542"
FT   DOMAIN          893..1020
FT                   /note="RLR CTR"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01125"
FT   REGION          271..307
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          640..662
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        271..291
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        644..659
FT                   /note="Acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   BINDING         907
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01125"
FT   BINDING         910
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01125"
FT   BINDING         962
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01125"
FT   BINDING         964
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01125"
FT   SITE            208..209
FT                   /note="Cleavage"
FT                   /evidence="ECO:0000250"
FT   SITE            216..217
FT                   /note="Cleavage"
FT                   /evidence="ECO:0000250"
FT   SITE            251..252
FT                   /note="Cleavage"
FT                   /evidence="ECO:0000250"
FT   MOD_RES         88
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:33727702"
FT   MOD_RES         289
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q8R5F7"
FT   MOD_RES         291
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q8R5F7"
FT   MOD_RES         301
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q8R5F7"
FT   MOD_RES         645
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q8R5F7"
FT   MOD_RES         828
FT                   /note="Phosphoserine; by RIOK3"
FT                   /evidence="ECO:0000269|PubMed:25865883"
FT   CROSSLNK        23
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ISG15)"
FT                   /evidence="ECO:0000269|PubMed:33727702"
FT   CROSSLNK        43
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ISG15)"
FT                   /evidence="ECO:0000269|PubMed:33727702"
FT   VAR_SEQ         208..221
FT                   /note="EIENLSQVDGPQVE -> GICNFTEEDSSNSA (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_013337"
FT   VAR_SEQ         222..1025
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_013338"
FT   VARIANT         337
FT                   /note="R -> G (in AGS7; enhances the interferon signaling
FT                   pathway activation; enhances the stability of filament
FT                   formation; enhances dsRNA binding activity; no loss of ATP
FT                   hydrolysis; dbSNP:rs587777447)"
FT                   /evidence="ECO:0000269|PubMed:24686847"
FT                   /id="VAR_071375"
FT   VARIANT         365
FT                   /note="K -> E (in IMD95; does not bind the double-stranded
FT                   RNA analog poly(I:C); loss of IFNB1 and NFKB promoter
FT                   activation after stimulation with poly(I:C), when tested in
FT                   a luciferase reporter assay)"
FT                   /evidence="ECO:0000269|PubMed:28606988"
FT                   /id="VAR_087007"
FT   VARIANT         372
FT                   /note="L -> F (in AGS7; enhances IFNB1 promoter activation;
FT                   loss of ligand-induced responsiveness; dbSNP:rs587777576)"
FT                   /evidence="ECO:0000269|PubMed:24995871"
FT                   /id="VAR_071376"
FT   VARIANT         393
FT                   /note="D -> V (in AGS7; enhances the interferon signaling
FT                   pathway activation; enhances the stability of filament
FT                   formation; enhances dsRNA binding activity; no loss of ATP
FT                   hydrolysis; dbSNP:rs587777449)"
FT                   /evidence="ECO:0000269|PubMed:24686847"
FT                   /id="VAR_071377"
FT   VARIANT         452
FT                   /note="A -> T (in AGS7; enhances IFNB1 promoter activation;
FT                   loss of ligand-induced responsiveness; dbSNP:rs587777575)"
FT                   /evidence="ECO:0000269|PubMed:24995871"
FT                   /id="VAR_071378"
FT   VARIANT         460
FT                   /note="H -> R (in dbSNP:rs10930046)"
FT                   /id="VAR_031226"
FT   VARIANT         495
FT                   /note="G -> R (in AGS7; enhances the interferon signaling
FT                   pathway activation; enhances the stability of filament
FT                   formation; enhances dsRNA binding activity; no loss of ATP
FT                   hydrolysis; dbSNP:rs672601336)"
FT                   /evidence="ECO:0000269|PubMed:24686847"
FT                   /id="VAR_071379"
FT   VARIANT         720
FT                   /note="R -> Q (in AGS7; enhances the interferon signaling
FT                   pathway activation; enhances the stability of filament
FT                   formation; enhances dsRNA binding activity; no loss of ATP
FT                   hydrolysis; dbSNP:rs587777445)"
FT                   /evidence="ECO:0000269|PubMed:24686847"
FT                   /id="VAR_071380"
FT   VARIANT         779
FT                   /note="R -> C (in AGS7; enhances the interferon signaling
FT                   pathway activation; enhances the stability of filament
FT                   formation; enhances dsRNA binding activity; no loss of ATP
FT                   hydrolysis; dbSNP:rs587777448)"
FT                   /evidence="ECO:0000269|PubMed:24686847"
FT                   /id="VAR_071381"
FT   VARIANT         779
FT                   /note="R -> H (in AGS7; enhances the interferon signaling
FT                   pathway activation; enhances the stability of filament
FT                   formation; enhances dsRNA binding activity; enhances IFNB1
FT                   promoter activation; no loss of ATP hydrolysis;
FT                   dbSNP:rs587777446)"
FT                   /evidence="ECO:0000269|PubMed:24686847,
FT                   ECO:0000269|PubMed:24995871"
FT                   /id="VAR_071382"
FT   VARIANT         822
FT                   /note="R -> Q (in SGMRT1; gain-of-function mutation
FT                   resulting in enhanced INFB1 induction; dbSNP:rs376048533)"
FT                   /evidence="ECO:0000269|PubMed:25620204"
FT                   /id="VAR_073666"
FT   VARIANT         843
FT                   /note="H -> R (in dbSNP:rs3747517)"
FT                   /evidence="ECO:0000269|PubMed:14645903,
FT                   ECO:0000269|PubMed:14702039, ECO:0000269|PubMed:15489334"
FT                   /id="VAR_021594"
FT   VARIANT         889..1025
FT                   /note="Missing (in IMD95; no protein detected by Western
FT                   blot in homozygous patient cells)"
FT                   /evidence="ECO:0000269|PubMed:29018476"
FT                   /id="VAR_087008"
FT   VARIANT         946
FT                   /note="A -> T (risk factor for T1D19; dbSNP:rs1990760)"
FT                   /evidence="ECO:0000269|PubMed:14702039,
FT                   ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:16699517"
FT                   /id="VAR_021595"
FT   MUTAGEN         23
FT                   /note="K->A: Loss of ISGylation, loss of oligomerization,
FT                   strongly reduced signaling activity and IFNB induction,
FT                   loss of virus replication restriction, no effect on
FT                   phosphorylation or RNA-binding; when associated with A-43."
FT                   /evidence="ECO:0000269|PubMed:33727702"
FT   MUTAGEN         43
FT                   /note="K->A: Loss of ISGylation, loss of oligomerization,
FT                   strongly reduced signaling activity and IFNB induction,
FT                   loss of virus replication restriction, no effect on
FT                   phosphorylation or RNA-binding; when associated with A-23."
FT                   /evidence="ECO:0000269|PubMed:33727702"
FT   MUTAGEN         68
FT                   /note="K->A: No effect on ISGylation or signaling activity
FT                   and IFNB induction."
FT                   /evidence="ECO:0000269|PubMed:33727702"
FT   MUTAGEN         74..75
FT                   /note="GW->AA: Loss of oligomerization."
FT                   /evidence="ECO:0000269|PubMed:33727702"
FT   MUTAGEN         88
FT                   /note="S->A: Increases ISGylation."
FT                   /evidence="ECO:0000269|PubMed:33727702"
FT   MUTAGEN         88
FT                   /note="S->E,D: Loss of signaling activity and IFNB
FT                   induction. Reduced ISGylation. Loss of virus replication
FT                   restriction."
FT                   /evidence="ECO:0000269|PubMed:33727702"
FT   MUTAGEN         251
FT                   /note="D->A: No cleavage and no acceleration of DNA
FT                   degradation."
FT                   /evidence="ECO:0000269|PubMed:12015121"
FT   MUTAGEN         335
FT                   /note="K->A: Loss of dsRNA-induced ATPase activity. No
FT                   effect on RNA binding. Changed MDA-5 signaling pathway."
FT                   /evidence="ECO:0000269|PubMed:19211564"
FT   MUTAGEN         443..446
FT                   /note="DECH->AACA: Loss of dsRNA-induced ATPase activity.
FT                   No effect on RNA binding. Changed MDA-5 signaling pathway."
FT                   /evidence="ECO:0000269|PubMed:19211564"
FT   MUTAGEN         444
FT                   /note="E->A: No acceleration of DNA degradation, no binding
FT                   to ATP, and no helicase activity."
FT                   /evidence="ECO:0000269|PubMed:12015121"
FT   MUTAGEN         488..490
FT                   /note="TAS->AAA: Loss of dsRNA-induced ATPase activity. No
FT                   effect on RNA binding. Changed MDA-5 signaling pathway."
FT                   /evidence="ECO:0000269|PubMed:19211564"
FT   MUTAGEN         789..793
FT                   /note="TTVAE->ATVAA: Loss of dsRNA-induced ATPase activity.
FT                   Loss of MDA-5 signaling pathway."
FT                   /evidence="ECO:0000269|PubMed:19211564"
FT   MUTAGEN         818..822
FT                   /note="QARGR->AARGA: Loss of dsRNA-induced ATPase activity.
FT                   No effect on MDA-5 signaling pathway."
FT                   /evidence="ECO:0000269|PubMed:19211564"
FT   MUTAGEN         828
FT                   /note="S->A: Promotes multimerization after polyI:C
FT                   stimulation; greatly enhances signaling."
FT                   /evidence="ECO:0000269|PubMed:25865883"
FT   MUTAGEN         828
FT                   /note="S->D: Inhibits multimerization after polyI:C
FT                   stimulation."
FT                   /evidence="ECO:0000269|PubMed:25865883"
FT   MUTAGEN         829
FT                   /note="T->A: Moderately increases signaling."
FT                   /evidence="ECO:0000269|PubMed:25865883"
FT   MUTAGEN         841..842
FT                   /note="IE->RR: Loss of oligomerization."
FT                   /evidence="ECO:0000269|PubMed:33727702"
FT   MUTAGEN         848..849
FT                   /note="DF->AA: Loss of oligomerization."
FT                   /evidence="ECO:0000269|PubMed:33727702"
FT   CONFLICT        439
FT                   /note="L -> F (in Ref. 2; AAG54076)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        475
FT                   /note="N -> H (in Ref. 4; BAB71141)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        592
FT                   /note="E -> K (in Ref. 1; AAG34368)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        598
FT                   /note="R -> S (in Ref. 2; AAG54076)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        609
FT                   /note="E -> K (in Ref. 2; AAG54076)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        782
FT                   /note="K -> R (in Ref. 4; BAB71141)"
FT                   /evidence="ECO:0000305"
FT   HELIX           8..17
FT                   /evidence="ECO:0007829|PDB:7DNI"
FT   HELIX           19..25
FT                   /evidence="ECO:0007829|PDB:7DNI"
FT   HELIX           28..31
FT                   /evidence="ECO:0007829|PDB:7DNI"
FT   TURN            32..34
FT                   /evidence="ECO:0007829|PDB:7DNI"
FT   HELIX           40..67
FT                   /evidence="ECO:0007829|PDB:7DNI"
FT   HELIX           75..85
FT                   /evidence="ECO:0007829|PDB:7DNI"
FT   HELIX           89..93
FT                   /evidence="ECO:0007829|PDB:7DNI"
FT   STRAND          97..99
FT                   /evidence="ECO:0007829|PDB:7DNI"
FT   HELIX           105..128
FT                   /evidence="ECO:0007829|PDB:7DNI"
FT   HELIX           131..141
FT                   /evidence="ECO:0007829|PDB:7DNI"
FT   HELIX           146..155
FT                   /evidence="ECO:0007829|PDB:7DNI"
FT   TURN            156..158
FT                   /evidence="ECO:0007829|PDB:7DNI"
FT   HELIX           160..170
FT                   /evidence="ECO:0007829|PDB:7DNI"
FT   HELIX           171..173
FT                   /evidence="ECO:0007829|PDB:7DNI"
FT   HELIX           177..186
FT                   /evidence="ECO:0007829|PDB:7DNI"
FT   TURN            187..189
FT                   /evidence="ECO:0007829|PDB:7DNI"
FT   HELIX           191..198
FT                   /evidence="ECO:0007829|PDB:7DNI"
FT   HELIX           293..299
FT                   /evidence="ECO:0007829|PDB:3B6E"
FT   HELIX           310..320
FT                   /evidence="ECO:0007829|PDB:3B6E"
FT   STRAND          325..328
FT                   /evidence="ECO:0007829|PDB:3B6E"
FT   HELIX           332..352
FT                   /evidence="ECO:0007829|PDB:3B6E"
FT   STRAND          359..365
FT                   /evidence="ECO:0007829|PDB:3B6E"
FT   HELIX           366..375
FT                   /evidence="ECO:0007829|PDB:3B6E"
FT   HELIX           377..381
FT                   /evidence="ECO:0007829|PDB:3B6E"
FT   TURN            382..384
FT                   /evidence="ECO:0007829|PDB:3B6E"
FT   STRAND          387..389
FT                   /evidence="ECO:0007829|PDB:3B6E"
FT   HELIX           400..406
FT                   /evidence="ECO:0007829|PDB:3B6E"
FT   STRAND          408..413
FT                   /evidence="ECO:0007829|PDB:3B6E"
FT   HELIX           414..422
FT                   /evidence="ECO:0007829|PDB:3B6E"
FT   HELIX           434..436
FT                   /evidence="ECO:0007829|PDB:3B6E"
FT   STRAND          438..442
FT                   /evidence="ECO:0007829|PDB:3B6E"
FT   HELIX           454..473
FT                   /evidence="ECO:0007829|PDB:3B6E"
FT   STRAND          483..488
FT                   /evidence="ECO:0007829|PDB:3B6E"
FT   HELIX           900..902
FT                   /evidence="ECO:0007829|PDB:3GA3"
FT   STRAND          903..907
FT                   /evidence="ECO:0007829|PDB:3GA3"
FT   TURN            908..910
FT                   /evidence="ECO:0007829|PDB:3GA3"
FT   STRAND          913..916
FT                   /evidence="ECO:0007829|PDB:3GA3"
FT   HELIX           917..919
FT                   /evidence="ECO:0007829|PDB:3GA3"
FT   STRAND          921..923
FT                   /evidence="ECO:0007829|PDB:3GA3"
FT   TURN            924..926
FT                   /evidence="ECO:0007829|PDB:3GA3"
FT   STRAND          927..929
FT                   /evidence="ECO:0007829|PDB:3GA3"
FT   HELIX           934..937
FT                   /evidence="ECO:0007829|PDB:3GA3"
FT   STRAND          938..942
FT                   /evidence="ECO:0007829|PDB:3GA3"
FT   TURN            945..947
FT                   /evidence="ECO:0007829|PDB:3GA3"
FT   STRAND          955..962
FT                   /evidence="ECO:0007829|PDB:3GA3"
FT   STRAND          967..974
FT                   /evidence="ECO:0007829|PDB:3GA3"
FT   STRAND          977..982
FT                   /evidence="ECO:0007829|PDB:3GA3"
FT   HELIX           984..986
FT                   /evidence="ECO:0007829|PDB:3GA3"
FT   STRAND          987..991
FT                   /evidence="ECO:0007829|PDB:3GA3"
FT   TURN            992..995
FT                   /evidence="ECO:0007829|PDB:3GA3"
FT   STRAND          996..998
FT                   /evidence="ECO:0007829|PDB:3GA3"
FT   HELIX           1003..1005
FT                   /evidence="ECO:0007829|PDB:3GA3"
FT   HELIX           1015..1017
FT                   /evidence="ECO:0007829|PDB:3GA3"
SQ   SEQUENCE   1025 AA;  116689 MW;  789CFB4824B92DC9 CRC64;
     MSNGYSTDEN FRYLISCFRA RVKMYIQVEP VLDYLTFLPA EVKEQIQRTV ATSGNMQAVE
     LLLSTLEKGV WHLGWTREFV EALRRTGSPL AARYMNPELT DLPSPSFENA HDEYLQLLNL
     LQPTLVDKLL VRDVLDKCME EELLTIEDRN RIAAAENNGN ESGVRELLKR IVQKENWFSA
     FLNVLRQTGN NELVQELTGS DCSESNAEIE NLSQVDGPQV EEQLLSTTVQ PNLEKEVWGM
     ENNSSESSFA DSSVVSESDT SLAEGSVSCL DESLGHNSNM GSDSGTMGSD SDEENVAARA
     SPEPELQLRP YQMEVAQPAL EGKNIIICLP TGSGKTRVAV YIAKDHLDKK KKASEPGKVI
     VLVNKVLLVE QLFRKEFQPF LKKWYRVIGL SGDTQLKISF PEVVKSCDII ISTAQILENS
     LLNLENGEDA GVQLSDFSLI IIDECHHTNK EAVYNNIMRH YLMQKLKNNR LKKENKPVIP
     LPQILGLTAS PGVGGATKQA KAEEHILKLC ANLDAFTIKT VKENLDQLKN QIQEPCKKFA
     IADATREDPF KEKLLEIMTR IQTYCQMSPM SDFGTQPYEQ WAIQMEKKAA KEGNRKERVC
     AEHLRKYNEA LQINDTIRMI DAYTHLETFY NEEKDKKFAV IEDDSDEGGD DEYCDGDEDE
     DDLKKPLKLD ETDRFLMTLF FENNKMLKRL AENPEYENEK LTKLRNTIME QYTRTEESAR
     GIIFTKTRQS AYALSQWITE NEKFAEVGVK AHHLIGAGHS SEFKPMTQNE QKEVISKFRT
     GKINLLIATT VAEEGLDIKE CNIVIRYGLV TNEIAMVQAR GRARADESTY VLVAHSGSGV
     IEHETVNDFR EKMMYKAIHC VQNMKPEEYA HKILELQMQS IMEKKMKTKR NIAKHYKNNP
     SLITFLCKNC SVLACSGEDI HVIEKMHHVN MTPEFKELYI VRENKALQKK CADYQINGEI
     ICKCGQAWGT MMVHKGLDLP CLKIRNFVVV FKNNSTKKQY KKWVELPITF PNLDYSECCL
     FSDED
//