RIGI

The RIGI protein (RIGI stands for "RNA Sensor RIG-I"; RIG is the acronym for: Retinoic Acid-Inducible Gene I Protein) is an intracellular receptor of the innate immune system that belongs to the helicases and is encoded by the RIGI gene of the same name. RIGI recognizes cytoplasmic viral nucleic acids and activates a downstream signaling 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 RNA helicase RIGI 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). The receptor 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.

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.