Interferon-induced helicase C domain-containing protein 1

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 pro-inflammatory 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), mengo encephalomyocarditis virus (ENMG), and rhinovirus. Detects coronavirus SARS-CoV-2. 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.

Classification

Family (Pfam)

PF16739 CARD_2, PF00271 Helicase_C, PF04851 ResIII, PF18119 RIG-I_C, PF11648 RIG-I_C-RD

InterPro

CARD_dom, DEATH-like_dom_sf, Helicase/UvrB_N, Helicase_ATP-bd, Helicase_C-like, P-loop_NTPase, RIG-I-like_C, RLR_C_sf, RLR_CTR, RLR_Helicase

Functional cluster

Phosphoribosyltransferases & related

Experimental structures · PDB · 8

• 2RQB NMR
• 3B6E X-ray 1.60A
• 3GA3 X-ray 1.45A
• 4GL2 X-ray 3.56A
• 7DNI EM 3.20A
• 7DNJ EM 3.30A
• 7JL0 EM 4.30A
• 7JL2 EM 4.30A

A predicted model is available from AlphaFold.

Gene Ontology · 34

• GO:0005737 cytoplasm
• GO:0005829 cytosol
• GO:0005739 mitochondrion
• GO:0005634 nucleus
• GO:0005524 ATP binding
• GO:0016887 ATP hydrolysis activity
• GO:0003677 DNA binding
• GO:0003725 double-stranded RNA binding
• GO:0042802 identical protein binding
• GO:0038187 pattern recognition receptor activity
• GO:0019904 protein domain specific binding
• GO:0043021 ribonucleoprotein complex binding
• GO:0003723 RNA binding
• GO:0003724 RNA helicase activity
• GO:0003727 single-stranded RNA binding
• GO:0008270 zinc ion binding
• GO:0140374 antiviral innate immune response
• GO:0071360 cellular response to exogenous dsRNA
• GO:0098586 cellular response to virus
• GO:0002753 cytoplasmic pattern recognition receptor signaling pathway
• GO:0051607 defense response to virus
• GO:0009597 detection of virus
• GO:0045087 innate immune response
• GO:0039530 MDA-5 signaling pathway
• GO:0045071 negative regulation of viral genome replication
• GO:0032727 positive regulation of interferon-alpha production
• GO:0032728 positive regulation of interferon-beta production
• GO:0032755 positive regulation of interleukin-6 production
• GO:0060760 positive regulation of response to cytokine stimulus
• GO:0032760 positive regulation of tumor necrosis factor production
• GO:0051259 protein complex oligomerization
• GO:0016925 protein sumoylation
• GO:0034344 regulation of type III interferon production
• GO:0009615 response to virus

Disease associations

• Singleton-Merten syndrome 1 MONDO:0024535
• type 1 diabetes mellitus 19 MONDO:0012422
• Aicardi-Goutieres syndrome 7 MONDO:0014367
• immunodeficiency 95 MONDO:0030692

Neighborhood · nearest proteins

Related proteins · sequence + function similarity

• Interferon-induced helicase C domain-containing protein 1 0.98
• Antiviral innate immune response receptor RIG-I 0.89
• Antiviral innate immune response receptor RIG-I 0.89
• Antiviral innate immune response receptor RIG-I 0.87
• ATP-dependent RNA helicase DHX58 0.71
• ATP-dependent RNA helicase DHX58 0.69
• E3 ubiquitin-protein ligase TTC3 0.60
• Endoribonuclease Dicer homolog 3a 0.59
• E3 ubiquitin-protein ligase TTC3 0.59
• ATP-dependent DNA helicase Q1 0.59
• Apoptotic protease-activating factor 1 0.59
• ATP-dependent DNA helicase Q1 0.59

Co-cited proteins · studied together in the literature

• Interferon-induced helicase C domain-containing protein 1 8 shared papers
• Antiviral innate immune response receptor RIG-I 18 shared papers
• ATP-dependent RNA helicase DHX58 8 shared papers
• Genome polyprotein 1 shared papers
• Serine/threonine-protein kinase RIO3 1 shared papers
• E3 ubiquitin ligase TRIM40 1 shared papers
• Mitochondrial antiviral-signaling protein 10 shared papers
• Antiviral innate immune response receptor RIG-I 3 shared papers
• Nucleotide-binding oligomerization domain-containing protein 1 1 shared papers
• E3 SUMO-protein ligase PIAS2 1 shared papers
• E3 ubiquitin-protein ligase TRIM65 1 shared papers
• E3 ubiquitin-protein ligase RNF123 1 shared papers

Literature · 56 cited papers

• ISG15-dependent activation of the sensor MDA5 is antagonized by the SARS-CoV-2 papain-like protease to evade host innate immunity. Nat. Microbiol. · 2021
• SARS-CoV-2 triggers an MDA-5-dependent interferon response which is unable to control replication in lung epithelial cells. J. Virol. · 2021
• MDA5 Governs the Innate Immune Response to SARS-CoV-2 in Lung Epithelial Cells. Cell Rep. · 2021
• NOD1 Promotes Antiviral Signaling by Binding Viral RNA and Regulating the Interaction of MDA5 and MAVS. J. Immunol. · 2020
• Encephalomyocarditis virus 2C protein antagonizes interferon-beta signaling pathway through interaction with MDA5. Antiviral Res. · 2018
• The zinc-finger protein ZCCHC3 binds RNA and facilitates viral RNA sensing and activation of the RIG-I-like receptors. Immunity · 2018
• The E3 Ubiquitin Ligase TRIM40 Attenuates Antiviral Immune Responses by Targeting MDA5 and RIG-I. Cell Rep. · 2017
• Recurrent and prolonged infections in a child with a homozygous IFIH1 nonsense mutation. Front. Genet. · 2017
• Recurrent rhinovirus infections in a child with inherited MDA5 deficiency. J. Exp. Med. · 2017
• ARRDC4 regulates enterovirus 71-induced innate immune response by promoting K63 polyubiquitination of MDA5 through TRIM65. Cell Death Dis. · 2017
• Disruption of MDA5-Mediated Innate Immune Responses by the 3C Proteins of Coxsackievirus A16, Coxsackievirus A6, and Enterovirus D68. J. Virol. · 2017
• RNF123 has an E3 ligase-independent function in RIG-I-like receptor-mediated antiviral signaling. EMBO Rep. · 2016
• … and 44 more in the literature graph