RIGIlike

RIG-I-like receptors (RLRs) are a family of cytosolic pattern recognition receptors that detect viral RNA and initiate innate immune responses. The best known members are RIG-I (DDX58), MDA5 (IFIH1), and LGP2 (DHX58). They play a central role in recognizing RNA viruses and shaping downstream antiviral signaling.

Structurally, RIG-I and MDA5 share an N-terminal pair of caspase activation and recruitment domains (CARDs), a central helicase-ATPase domain, and a C-terminal regulatory domain. LGP2 lacks the CARDs and therefore cannot signal on its own, but it modulates RLR activity. RIG-I preferentially binds to RNA with 5′-triphosphate and short double-stranded regions, while MDA5 detects long double-stranded RNA. Ligand binding induces conformational changes that expose the CARDs for signaling; LGP2 influences this process in a context-dependent manner.

Activation of RLR signaling begins when exposed CARDs interact with the adaptor protein MAVS on mitochondria and peroxisomes. This triggers downstream cascades through TBK1/IKKε and IKKα/β, leading to phosphorylation and activation of transcription factors IRF3/7 and NF-κB. The result is the production of type I interferons and proinflammatory cytokines, establishing an antiviral state and shaping subsequent adaptive responses.

Regulation and clinical relevance: RLR signaling is tightly controlled by ubiquitination, phosphorylation, and various regulatory proteins, including TRIM25 and RIPLET that modulate RIG-I activation. Dysregulation of RLR pathways is associated with increased susceptibility to viral infections and with autoimmune or autoinflammatory conditions. Because of their central role in antiviral defense, RLRs are a focus of research into vaccines, antiviral therapies, and cancer immunotherapy.