Antiviral innate immune response receptor RIG-I

Function

Innate immune receptor that senses cytoplasmic viral nucleic acids and activates a downstream signaling cascade leading to the production of type I interferons and pro-inflammatory cytokines. Forms a ribonucleoprotein complex with viral RNAs on which it homooligomerizes to form filaments. The homooligomerization allows the recruitment of RNF135 an E3 ubiquitin-protein ligase that activates and amplifies the RIG-I-mediated antiviral signaling in an RNA length-dependent manner through ubiquitination-dependent and -independent mechanisms. Upon activation, associates with mitochondria antiviral signaling protein (MAVS/IPS1) that activates the IKK-related kinases TBK1 and IKBKE which in turn phosphorylate the interferon regulatory factors IRF3 and IRF7, activating transcription of antiviral immunological genes including the IFN-alpha and IFN-beta interferons. Ligands include 5'-triphosphorylated ssRNAs and dsRNAs but also short dsRNAs (<1 kb in length). In addition to the 5'-triphosphate moiety, blunt-end base pairing at the 5'-end of the RNA is very essential. Overhangs at the non-triphosphorylated end of the dsRNA RNA have no major impact on its activity. A 3'overhang at the 5'triphosphate end decreases and any 5'overhang at the 5' triphosphate end abolishes its activity. Detects both positive and negative strand RNA viruses including members of the families Paramyxoviridae: Human respiratory syncytial virus and measles virus (MeV), Rhabdoviridae: vesicular stomatitis virus (VSV), Orthomyxoviridae: influenza A and B virus, Flaviviridae: Japanese encephalitis virus (JEV), hepatitis C virus (HCV), dengue virus (DENV) and west Nile virus (WNV). It also detects rotaviruses and reoviruses. Detects and binds to SARS-CoV-2 RNAs which is inhibited by m6A RNA modifications (Ref.74). Also involved in antiviral signaling in response to viruses containing a dsDNA genome such as Epstein-Barr virus (EBV). Detects dsRNA produced from non-self dsDNA by RNA polymerase III, such as Epstein-Barr virus-encoded RNAs (EBERs). May play important roles in granulocyte production and differentiation, bacterial phagocytosis and in the regulation of cell migration.

Classification

Family (Pfam)

PF16739 CARD_2, PF00270 DEAD, PF00271 Helicase_C, PF18119 RIG-I_C, PF11648 RIG-I_C-RD

InterPro

CARD_dom, CARD_RIG-I_r2, DEAD/DEAH_box_helicase_dom, DEATH-like_dom_sf, 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 · 44

• 2LWD NMR
• 2LWE NMR
• 2QFB X-ray 3.00A
• 2QFD X-ray 2.70A
• 2RMJ NMR
• 2YKG X-ray 2.50A
• 3LRN X-ray 2.60A
• 3LRR X-ray 2.15A
• 3NCU X-ray 2.55A
• 3OG8 X-ray 2.40A
• 3ZD6 X-ray 2.80A
• 3ZD7 X-ray 2.50A
• … and 32 more

A predicted model is available from AlphaFold.

Gene Ontology · 41

• GO:0015629 actin cytoskeleton
• GO:0005923 bicellular tight junction
• GO:0005737 cytoplasm
• GO:0005829 cytosol
• GO:0005886 plasma membrane
• GO:1990904 ribonucleoprotein complex
• GO:0032587 ruffle membrane
• GO:0005524 ATP binding
• GO:0016887 ATP hydrolysis activity
• GO:0003690 double-stranded DNA binding
• GO:0003725 double-stranded RNA binding
• GO:0005525 GTP binding
• GO:0042802 identical protein binding
• GO:0038187 pattern recognition receptor activity
• GO:0003724 RNA helicase activity
• GO:0003727 single-stranded RNA binding
• GO:0031625 ubiquitin protein ligase binding
• GO:0008270 zinc ion binding
• GO:0140374 antiviral innate immune response
• GO:0071360 cellular response to exogenous dsRNA
• GO:0002753 cytoplasmic pattern recognition receptor signaling pathway
• GO:0051607 defense response to virus
• GO:0009597 detection of virus
• GO:0010467 gene expression
• GO:0045087 innate immune response
• GO:0002230 positive regulation of defense response to virus by host
• GO:0010628 positive regulation of gene expression
• GO:0032725 positive regulation of granulocyte macrophage colony-stimulating factor production
• 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:0032757 positive regulation of interleukin-8 production
• GO:0002735 positive regulation of myeloid dendritic cell cytokine production
• GO:0060760 positive regulation of response to cytokine stimulus
• GO:0045944 positive regulation of transcription by RNA polymerase II
• GO:0032760 positive regulation of tumor necrosis factor production
• GO:0030334 regulation of cell migration
• GO:0034344 regulation of type III interferon production
• GO:0043330 response to exogenous dsRNA
• GO:0009615 response to virus
• GO:0039529 RIG-I signaling pathway

Disease associations

• Singleton-Merten syndrome 2 MONDO:0014575

Neighborhood · nearest proteins

Related proteins · sequence + function similarity

• Antiviral innate immune response receptor RIG-I 0.98
• Antiviral innate immune response receptor RIG-I 0.98
• Interferon-induced helicase C domain-containing protein 1 0.90
• Interferon-induced helicase C domain-containing protein 1 0.89
• ATP-dependent RNA helicase DHX58 0.75
• ATP-dependent RNA helicase DHX58 0.71
• NLR family CARD domain-containing protein 4 0.62
• E3 ubiquitin-protein ligase TTC3 0.62
• Apoptotic protease-activating factor 1 0.62
• Endoribonuclease Dicer homolog 3a 0.62
• Apoptotic protease-activating factor 1 0.62
• Nuclear GTPase SLIP-GC 0.61

Co-cited proteins · studied together in the literature

• Interferon-induced helicase C domain-containing protein 1 18 shared papers
• E3 ubiquitin-protein ligase RNF135 5 shared papers
• Antiviral innate immune response receptor RIG-I 7 shared papers
• E3 ubiquitin/ISG15 ligase TRIM25 7 shared papers
• ADP-ribosylation factor-like protein 16 1 shared papers
• Mitochondrial antiviral-signaling protein 14 shared papers
• E3 ubiquitin-protein ligase TRIM4 1 shared papers
• SEC14-like protein 1 1 shared papers
• Interferon alpha-inducible protein 6 1 shared papers
• Probable ATP-dependent RNA helicase DHX35 1 shared papers
• Inner tegument protein 1 shared papers
• Ubiquitin carboxyl-terminal hydrolase 3 1 shared papers

Literature · 79 cited papers

• The RNA helicase DHX35 functions as a co-sensor for RIG-I-mediated innate immunity. PLoS Pathog. · 2024
• Interferon alpha inducible protein 6 is a negative regulator of innate immune responses by modulating RIG-I activation. Front. Immunol. · 2023
• The RNA helicase DHX16 recognizes specific viral RNA to trigger RIG-I-dependent innate antiviral immunity. Cell Rep. · 2022
• The US3 Kinase of Herpes Simplex Virus Phosphorylates the RNA Sensor RIG-I To Suppress Innate Immunity. J. Virol. · 2022
• RTN3 inhibits RIG-I-mediated antiviral responses by impairing TRIM25-mediated K63-linked polyubiquitination. Elife · 2021
• Autoimmunity gene IRGM suppresses cGAS-STING and RIG-I-MAVS signaling to control interferon response. EMBO Rep. · 2020
• USP27X negatively regulates antiviral signaling by deubiquitinating RIG-I. PLoS Pathog. · 2020
• Dual targeting of RIG-I and MAVS by MARCH5 mitochondria ubiquitin ligase in innate immunity. Cell. Signal. · 2020
• Ubiquitin-Dependent and -Independent Roles of E3 Ligase RIPLET in Innate Immunity. Cell · 2019
• The zinc-finger protein ZCCHC3 binds RNA and facilitates viral RNA sensing and activation of the RIG-I-like receptors. Immunity · 2018
• Paramyxovirus V Proteins Interact with the RIG-I/TRIM25 Regulatory Complex and Inhibit RIG-I Signaling. J. Virol. · 2018
• LRRC25 inhibits type I IFN signaling by targeting ISG15-associated RIG-I for autophagic degradation. EMBO J. · 2018
• … and 67 more in the literature graph