- RIG‑I (Retinoic Acid‑Inducible Gene I) is one of the most important pattern‑recognition receptors in innate immunity. It acts as a cytosolic sensor that detects viral RNA and initiates a powerful antiviral response through interferon production and inflammatory signalling. RIG‑I belongs to the RIG‑I‑like receptor (RLR) family, alongside MDA5 and LGP2, but it is unique in its ability to recognise short viral RNA fragments containing 5′‑triphosphate or 5′‑diphosphate ends. This specificity allows RIG‑I to detect a wide range of RNA viruses, including influenza, rabies, hepatitis C virus, and many negative‑strand RNA viruses.
- Structurally, RIG‑I contains two N‑terminal CARD domains, a central helicase domain, and a C‑terminal regulatory domain. In the resting state, the CARD domains are folded back against the helicase core, keeping RIG‑I autoinhibited. When viral RNA binds to the helicase and C‑terminal domains, ATP‑driven conformational changes expose the CARD domains, enabling them to initiate downstream signalling. This exposure is essential but not sufficient; the CARD domains must undergo K63‑linked ubiquitination to become fully active.
- The E3 ubiquitin ligase TRIM25 plays a central role in RIG‑I activation. TRIM25 binds directly to CARD2 and assembles K63‑linked polyubiquitin chains that stabilise the active conformation of RIG‑I. These chains do not target RIG‑I for degradation; instead, they act as structural scaffolds that promote interaction with MAVS, the mitochondrial antiviral signalling protein. Other TRIM ligases, including TRIM4 and TRIM65, can also modify RIG‑I, but TRIM25 is the primary regulator in most cell types.
- Once ubiquitinated, the exposed CARD domains bind MAVS on the outer mitochondrial membrane. This interaction triggers MAVS polymerisation into filamentous signalling complexes that activate TBK1, IKKε and downstream transcription factors such as IRF3, IRF7 and NF‑κB. The result is robust production of type I interferons and inflammatory cytokines, establishing an antiviral state in infected and neighbouring cells. Through this pathway, RIG‑I acts as a molecular switch that converts viral RNA detection into a full immune response.
- Because RIG‑I is so central to antiviral defence, many viruses have evolved strategies to inhibit its activation. Influenza A virus NS1 protein binds TRIM25 and prevents CARD ubiquitination. SARS‑CoV‑2 nucleocapsid protein interferes with TRIM25 and RIG‑I signalling. Hepatitis C virus NS3/4A protease cleaves MAVS, severing the connection between RIG‑I and downstream signalling. These antagonistic mechanisms highlight the importance of RIG‑I as a bottleneck in antiviral immunity.
- Beyond classical antiviral signalling, RIG‑I also participates in broader cellular processes, including apoptosis, inflammasome activation and regulation of RNA metabolism. Its ability to distinguish self from non‑self RNA makes it a key guardian of cellular integrity. Dysregulation of RIG‑I signalling has been linked to autoimmune disorders, chronic inflammation and certain cancers, underscoring its clinical relevance.
- In summary, RIG‑I is a highly specialised cytosolic receptor that detects viral RNA and triggers powerful antiviral responses. Its activation depends on RNA binding, ATP‑driven conformational changes and TRIM25‑mediated ubiquitination of the CARD domains. Through MAVS signalling, RIG‑I orchestrates interferon production and inflammatory responses that protect the host from viral infection. As research continues to uncover new layers of regulation, RIG‑I remains a central focus in immunology, virology and therapeutic development.
