ID:IFIH1_HUMAN DESCRIPTION: RecName: Full=Interferon-induced helicase C domain-containing protein 1; EC=3.6.4.13; AltName: Full=Clinically amyopathic dermatomyositis autoantigen 140 kDa; Short=CADM-140 autoantigen; AltName: Full=Helicase with 2 CARD domains; Short=Helicard; AltName: Full=Interferon-induced with helicase C domain protein 1; AltName: Full=Melanoma differentiation-associated protein 5; Short=MDA-5; AltName: Full=Murabutide down-regulated protein; AltName: Full=RIG-I-like receptor 2; Short=RLR-2; AltName: Full=RNA helicase-DEAD box protein 116; FUNCTION: Innate immune receptor which acts as a cytoplasmic sensor of viral nucleic acids and plays a major role in sensing viral infection and in the activation of a cascade of antiviral responses including the induction of type I interferons and proinflammatory cytokines. Its ligands include mRNA lacking 2'-O- methylation at their 5' cap and long-dsRNA (>1 kb in length). Upon ligand binding it associates with mitochondria antiviral signaling protein (MAVS/IPS1) which activates the IKK-related kinases: TBK1 and IKBKE which phosphorylate interferon regulatory factors: IRF3 and IRF7 which in turn activate transcription of antiviral immunological genes, including interferons (IFNs); IFN-alpha and IFN-beta. Responsible for detecting the Picornaviridae family members such as encephalomyocarditis virus (EMCV) and mengo encephalomyocarditis virus (ENMG). Can also detect other viruses such as dengue virus (DENV), west Nile virus (WNV), and reovirus. Also involved in antiviral signaling in response to viruses containing a dsDNA genome, such as vaccinia virus. Plays an important role in amplifying innate immune signaling through recognition of RNA metabolites that are produced during virus infection by ribonuclease L (RNase L). May play an important role in enhancing natural killer cell function and may be involved in growth inhibition and apoptosis in several tumor cell lines. CATALYTIC ACTIVITY: ATP + H(2)O = ADP + phosphate. COFACTOR: Zinc. SUBUNIT: Monomer in the absence of ligands and homodimerizes in the presence of dsRNA ligands. Can assemble into helical or linear polymeric filaments on long dsRNA. Interacts with MAVS/IPS1. Interacts with V protein of Simian virus 5, Human parainfluenza virus 2, Mumps virus, Sendai virus and Hendra virus. Binding to paramyxoviruses V proteins prevents IFN-beta induction, and the further establishment of an antiviral state. Interacts with PCBP2. Interacts with NLRC5. Interacts with PIAS2-beta. Interacts with DDX60. SUBCELLULAR LOCATION: Cytoplasm. Nucleus (Potential). Note=May be found in the nucleus, during apoptosis. TISSUE SPECIFICITY: Widely expressed, at a low level. Expression is detected at slightly highest levels in placenta, pancreas and spleen and at barely levels in detectable brain, testis and lung. INDUCTION: By interferon (IFN) and TNF. PTM: During apoptosis, processed into 3 cleavage products. The helicase-containing fragment, once liberated from the CARD domains, translocate from the cytoplasm to the nucleus. The processed protein significantly sensitizes cells to DNA degradation (By similarity). PTM: Sumoylated. Sumoylation positively regulates its role in type I interferon induction and is enhanced by PIAS2-beta. DISEASE: Genetic variation in IFIH1 is associated with diabetes mellitus insulin-dependent type 19 (IDDM19) [MIM:610155]. A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical fetaures are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. DISEASE: Note=IFIH1 is the CADM-140 autoantigen, involved in clinically amyopathic dermatomyositis (CADM). This is a chronic inflammatory disorder that shows typical skin manifestations of dermatomyositis but has no or little evidence of clinical myositis. Anti-CADM-140 antibodies appear to be specific to dermatomyositis, especially CADM. Patients with anti-CADM-140 antibodies frequently develop life-threatening acute progressive interstitial lung disease (ILD). MISCELLANEOUS: In HIV-1 infected HeLa-CD4 cells, overexpression of IFIH1 results in a great increase in the level of secreted viral p24 protein. SIMILARITY: Belongs to the helicase family. RLR subfamily. SIMILARITY: Contains 2 CARD domains. SIMILARITY: Contains 1 helicase ATP-binding domain. SIMILARITY: Contains 1 helicase C-terminal domain. SEQUENCE CAUTION: Sequence=AAH78180.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence; Sequence=BAB71141.1; Type=Erroneous initiation;
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q9BYX4
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0002376 immune system process GO:0009597 detection of virus GO:0009615 response to virus GO:0016032 viral process GO:0016579 protein deubiquitination GO:0016925 protein sumoylation GO:0032480 negative regulation of type I interferon production GO:0032727 positive regulation of interferon-alpha production GO:0032728 positive regulation of interferon-beta production GO:0034344 regulation of type III interferon production GO:0035549 positive regulation of interferon-beta secretion GO:0039528 cytoplasmic pattern recognition receptor signaling pathway in response to virus GO:0039530 MDA-5 signaling pathway GO:0045087 innate immune response GO:0051607 defense response to virus GO:0060760 positive regulation of response to cytokine stimulus GO:0071360 cellular response to exogenous dsRNA GO:1902741 positive regulation of interferon-alpha secretion GO:1904469 positive regulation of tumor necrosis factor secretion GO:2000778 positive regulation of interleukin-6 secretion
AK056293 - Homo sapiens cDNA FLJ31731 fis, clone NT2RI2006855, weakly similar to Homo sapiens RNA helicase (RIG-I) mRNA. AF095844 - Homo sapiens melanoma differentiation associated protein-5 (MDA5) mRNA, complete cds. LQ878895 - Sequence 10 from Patent WO2018154075. AY017378 - Homo sapiens RNA helicase-DEAD box protein RH116 mRNA, complete cds. JD059204 - Sequence 40228 from Patent EP1572962. BC111750 - Homo sapiens interferon induced with helicase C domain 1, mRNA (cDNA clone MGC:133047 IMAGE:40008600), complete cds. AK292941 - Homo sapiens cDNA FLJ78660 complete cds, highly similar to Homo sapiens interferon induced with helicase C domain 1 (IFIH1), mRNA. AK314611 - Homo sapiens cDNA, FLJ95450. KJ899445 - Synthetic construct Homo sapiens clone ccsbBroadEn_08839 IFIH1 gene, encodes complete protein. BC078180 - Homo sapiens interferon induced with helicase C domain 1, mRNA (cDNA clone IMAGE:6502757), partial cds. BC007966 - Homo sapiens interferon induced with helicase C domain 1, mRNA (cDNA clone IMAGE:4304805), partial cds. BC046208 - Homo sapiens interferon induced with helicase C domain 1, mRNA (cDNA clone IMAGE:6176741), complete cds. CU692330 - Synthetic construct Homo sapiens gateway clone IMAGE:100022709 5' read IFIH1 mRNA. KJ903056 - Synthetic construct Homo sapiens clone ccsbBroadEn_12450 IFIH1 gene, encodes complete protein. JD114132 - Sequence 95156 from Patent EP1572962. JD473470 - Sequence 454494 from Patent EP1572962.
Biochemical and Signaling Pathways
Reactome (by CSHL, EBI, and GO)
Protein Q9BYX4 (Reactome details) participates in the following event(s):
R-HSA-913725 viral dsRNA binds IFIH1:DAK R-HSA-168909 viral dsRNA:IFIH1, viral dsRNA:K63polyUb-DDX58 bind MAVS R-HSA-936378 Inhibition of DDX58/IFIH1 signaling by ATG5:ATG12:MAVS R-HSA-937343 NLRC5 interacts with DDX58/IFIH1 R-HSA-5696600 USP17 deubiquitinates RCE1, CDC25A, DDX58, IFIH1 R-HSA-168934 MAVS interacts with RIPK1 and FADD R-HSA-918227 Recruitment of TRAF3 to MAVS R-HSA-918230 Recruitment of TRAF6/TRAF2 to IPS-1 R-HSA-990528 Interaction of PCBP2 with MAVS R-HSA-933528 Interaction of MEKK1 with TRAF6 R-HSA-933537 Recruitment of TANK to TRAF6 R-HSA-933539 Recruitment of IKK complex R-HSA-918225 TBK1/IKK epsilon complex interacts with MAVS bound TRAF3 R-HSA-936381 OTUD5 deubiquitinates TRAF3 R-HSA-933526 Recruitment of caspase-8 and -10 to FADD complex R-HSA-990526 Recruitment of AIP4 and K48 ubiquitination of MAVS/IPS-1 R-HSA-933527 Recruitment of TBK1/IKK epsilon complex to TANK:TRAF6 R-HSA-918232 Recruitment of IRF3,IRF7 R-HSA-918229 Phosphorylation and release of IRF3/IRF7 R-HSA-933523 Dimerzation of procaspase-8, procaspase-10 R-HSA-933538 Recruitment of IRF7 to TRAF6 R-HSA-933525 Phosphorylation and release of IRF7 R-HSA-933530 Activation of IKK by MEKK1 R-HSA-933532 Processing of caspases R-HSA-168928 DDX58/IFIH1-mediated induction of interferon-alpha/beta R-HSA-936440 Negative regulators of DDX58/IFIH1 signaling R-HSA-168249 Innate Immune System R-HSA-5689880 Ub-specific processing proteases R-HSA-933543 NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 R-HSA-918233 TRAF3-dependent IRF activation pathway R-HSA-933541 TRAF6 mediated IRF7 activation R-HSA-933542 TRAF6 mediated NF-kB activation R-HSA-168256 Immune System R-HSA-5688426 Deubiquitination R-HSA-5689896 Ovarian tumor domain proteases R-HSA-597592 Post-translational protein modification R-HSA-392499 Metabolism of proteins
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Common Gene Haplotype Alleles 
