Retinoic acid-inducible gene 1 (RIG-I) is a cytoplasmic RNA helicase member of the RIG-I-like receptor (RLR) family of proteins. RIG-I is highly conserved within vertebrates. Structurally, RIG-I is comprised of three main functional domains – Caspase Activation and Recruitment Domain (CARD) for signal transduction, DExD/ H-box RNA helicase domain, and C-terminal domain for RNA binding¹. The RNA helicase domain is associated with RNA-dependent ATP hydrolysis activities, which are essential in inducing a conformational change that exposes the CARD domain for signaling. RIG-I is usually well-regulated to prevent detrimental downstream inflammatory responses in the absence of a bona fide infection to allow for rapid recognition of pathogens².
RIG-I, Nucleic Acid Immunity, and Viral Infections
The RLR family of proteins are critical sensors of RNA viral infections – they recognize double-stranded RNA, 4-triphosphorylated RNAs, and other nucleic acid structures that are pathogen-associated molecular patterns (PAMPs) that indicate the presence of a viral infection. Almost all major families of viruses are recognized by RLRs1 – Influenza A, Hepatitis C, Sendai Virus, Vesicular Stomatitis Virus, Dengue Virus, etc. Upon the detection of virus infection, RIG-I initiates antiviral host defense by triggering the rapid induction of type 1 Interferon (IFN)³. This immune response relies on RNA sensors like RIG-I and is a component of the nucleic acid-directed immunity, which plays an integral role in detecting and eliminating nucleic acids of foreign origins which are introduced into the body by pathogens such as viruses4.
Viruses have been found to modify their genomic RNA to avoid being sensed by RIG-I. Others have developed ways to evade RIG-I detection by producing proteins that bind to and antagonize RIG-I resulting in RIG-I inactivation².
Type 1 Interferon (IFN) Responses
RIG-I induces Type 1 IFN responses via NFkB and IRF3 signaling pathways. RIG-I first physically associates with viral RNA, which causes several conformation changes, resulting in the activation of downstream signaling molecules and ultimately activating key transcription factors NFkB and IRF3. NFkB and IRF3 are responsible for producing Type 1 IFNs and other inflammatory cytokines. Type 1 IFNs, together with IFN-stimulated genes, promote cell death in infected cells and activate adaptive immune cells such as T helper cells and antibody production by B cells5. Additionally, RIG-I was found to directly initiate immune responses by forming an ‘inflammasome’ complex with apoptosis-associated speck-like protein containing CARD (ASC) and caspase-12.
RIG-I and Complex Auto-immune Disorders
Individuals with RLR deficiencies have reduced production of IFN, which will lead to increased susceptibility to viral infections and reduced immune responses. In contrast, the hyperactivation/ chronic activation of RLR-mediated signaling leads to auto-immunity. For example, mutations in the gene that codes for RIG-I cause a rare autoimmune disorder called Singleton-Merten syndrome (SMS). SMS is characterized by dental dysplasia and vessel calcifications, skeletal abnormalities, glaucoma, etc. The mutation resulted in the constitutive activation of RIG-I, which leads to the upregulation of IFN activity and expression of IFN-stimulated genes6.
1. Rehwinkel, J. & Gack, M. U. RIG-I-like receptors: their regulation and roles in RNA sensing. Nat Rev Immunol 20, 537–551 (2020).
2. Kato, H. & Fujita, T. Cytoplasmic Viral RNA Sensors: RIG-I-Like Receptors. in Encyclopedia of Immunobiology (ed. Ratcliffe, M. J. H.) 352–359 (Academic Press, 2016). doi:10.1016/B978-0-12-374279-7.02005-1.
3. Kato, H. et al. Cell Type-Specific Involvement of RIG-I in Antiviral Response. Immunity 23, 19–28 (2005).
4. Hartmann, G. Chapter Four – Nucleic Acid Immunity. in Advances in Immunology (ed. Alt, F. W.) vol. 133 121–169 (Academic Press, 2017).
5. Ivashkiv, L. B. & Donlin, L. T. Regulation of type I interferon responses. Nat Rev Immunol 14, 36–49 (2014).
6. Kato, H., Oh, S.-W. & Fujita, T. RIG-I-Like Receptors and Type I Interferonopathies. J Interferon Cytokine Res 37, 207–213 (2017).