Alt. symbols: DDX58 | RIG-I | FLJ13599 | DKFZp434J1111 | RIG-1 | RIG1

Approved name: RNA sensor RIG-I
Alt. names: DEAD (Asp-Glu-Ala-Asp) box polypeptide 58 | RNA helicase RIG-I, retinoic acid inducible gene I

Location: 9p21.1: 32455302 - 32526348 (-)
Gene type: protein_coding, 13 transcripts.

Scores: LoFtool: 0.983000 | pLI: 0.00000000 | LOEUF:

HGNC: 19102

NCBI: 23586, RefSeq: NG_046918.1

Ensembl: ENSG00000107201.12

LRG_ | Status: none

OMIM: 609631

Expression | ProteinAtlas

The most common receptors for the induction of type I IFN signaling in response to viral RNA sensing are the RIG-I (retinoic acid–inducible gene I) like receptors RIG-I (encoded by DDX58) and MDA5 (encoded by IFIH1). These receptors induce the transcription of type I IFN genes via mitochondrial antiviral signaling proteins (MAVS) followed by NF-κB, IRF3, and AP-1 signaling and pro-inflammatory cytokine production. RIG-I protein contains RNA helicase-DEAD box protein motifs and a caspase recruitment domain (CARD), the former important for sensing cytoplasmic viral nucleic acids and the latter important for regulation of the subsequent innate immune response. DDX58 can detect both positive and negative strand RNA viruses including members of the families Paramyxoviridae (e.g. measles virus), Rhabdoviridae (e.g. vesicular stomatitis virus), Orthomyxoviridae (e.g. influenza A and B), Flaviviridae (e.g. Japanese encephalitis virus), hepatitis C virus, dengue virus, and west Nile virus. It also detects rotaviruses and reoviruses, and is involved in antiviral signaling in response to viruses containing a dsDNA genome such as EBV. It may also play important roles in granulocyte production and differentiation, bacterial phagocytosis and in the regulation of cell migration.

Gain-of-function (GOF) mutations in the RIG-I like receptor genes IFIH1 or RIGI have been associated with type I interferonopathies such as Singleton-Merten syndrome (SMS), Systemic Lupus Erythematosus (SLE) or Aicardi-Goutieres syndrome (AGS). Patients carrying mono-allelic GOF mutations show constitutive activation, increased type I IFN production and IFN-stimulated gene expression (PMID: 30047865, 30560918, 25620203) but without reported autoimmune manifestations. Though historically thought that classic SMS results from mutations in IFIH1 (PMID: 25620204), while RIGI mutations cause an atypical SMS with variable expression of glaucoma, aortic calcification, and skeletal abnormalities without dental anomalies, it's now becoming clear that the SMS clinical spectrum is shared across these genotypes. Some RIGI polymorphisms have been associated with multiple sclerosis and dermatomyositis (PMID: 19450885, 24604766). Most recently, Lee et al. (2024) from the Zhang/Casanova lab identified rare heterozygous hypermorphic / GOF variants in RIGI in 4 children with multisystem inflammatory syndrome (MIS-C), from an international cohort of 1000 MIS-C patients and 350 age-matched infected controls. These variants were distinct from those previously reported in SMS patients, and functionally less potent in vitro. This finding supported their hypothesis that enhanced RIG-I/MDA5–MAVS-driven inflammation in mononuclear phagocytes may be a key factor in the pathogenesis of this post-viral acute inflammatory syndrome. [Publication pending, presented at ESID 2024] [Load More]