RIGI gene

The RIGI gene (RIGI stands for. RNA Sensor RIG-I; RIG is the acronym for: Retinoic Acid-Inducible Gene I Protein) is a protein-coding gene located on chromosome 9p21.1. The natural ligand of RIG-I was only identified in 2006. Single- and double-stranded ribonucleic acids with a triphosphate at the 5'-end are recognized. This triphosphate RNA is produced by viral polymerases and cellular RNA polymerase III. RIG-I is activated by interferon-α, -β, -γ and bacterial lipopolysaccharides.

The RIGI gene encodes an intracellular receptor of the innate immune system belonging to the helicases, which recognizes cytoplasmic viral nucleic acids and activates a downstream signalling cascade that leads to the production of type I interferons and pro-inflammatory cytokines (Yoneyama M et al. 2004; Villamayor L et al. 2023). The encoded protein, an RNA helicase, contains "DEAD-box protein motifs" and a "caspase recruitment domain(CARD)". It is involved in the recognition of viral double-stranded (ds) RNA and in the regulation of the antiviral innate immune response.

RIGI forms a ribonucleoprotein complex with viral RNAs on which it homooligomerizes and forms filaments (Sumpter R Jr et al. 2005). Homooligomerization enables the recruitment of RNF135, an E3 ubiquitin-protein ligase that activates and amplifies RIG-I-mediated antiviral signaling in an RNA length-dependent manner through ubiquitination-dependent and -independent mechanisms. Upon activation, it associates with the mitochondrial antiviral signaling protein (MAVS/IPS1), which activates the IKK-related kinases TBK1 and IKBKE, which in turn phosphorylate the interferon-regulatory factors IRF3 and IRF7, activating the transcription of antiviral immunological genes including the interferons IFN-alpha and IFN-beta (Cadena C et al. 2019).

The ligands include 5'-triphosphorylated ssRNAs and dsRNAs, but also short dsRNAs (<1 kb in length). The receptor protein recognizes 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 (Kato H et al. 2011).

Furthermore, the receptor recognizes and binds to SARS-CoV-2 RNAs that are inhibited by m6A RNA modifications. It is also involved in antiviral signaling in response to viruses with a dsDNA genome such as Epstein-Barr virus (EBV) (Chiu YH et al. 2009). RIGI recognizes dsRNA produced by RNA polymerase III from foreign dsDNA, such as RNAs encoded by Epstein-Barr virus. May play an important role in the production and differentiation of granulocytes, in bacterial phagocytosis and in the regulation of cell migration.

Mutations in this gene are associated with Singleton-Merten syndrome, which is classified as a type 1 interferonopathy.

1. Cadena C et al. (2019) Ubiquitin-Dependent and -Independent Roles of E3 Ligase RIPLET in Innate Immunity. Cell 177:1187-1200.e16.
2. Chiu YH et al. (2009) RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell 138:576-591.
3. Kato H et al. (2011) RIG-I-like receptors: cytoplasmic sensors for non-self RNA. Immunol Rev 243:91-98.
4. Sumpter R Jr et al. (2005) Regulating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I. J Virol 79:2689-2699.
5. Villamayor L et al. (2023) Interferon alpha inducible protein 6 is a negative regulator of innate immune responses by modulating RIG-I activation. Front Immunol14:1105309.
6. Yoneyama M et al. (2004) The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 5:730-737.