Induction of type I interferon by RNA viruses: cellular receptors and their substrates

Baum, Alina; García-Sastre, Adolfo

Discovered in 2004, the RLR family of cytoplasmic viral sensors has become a major focus of research in antiviral innate immunity. The family is composed of three members, RIG-I, MDA5, and Laboratory of Genetic and Physiology 2 (LGP2). Both RIG-I and MDA5 belong to the family of DExD/H RNA helicases and contain a typical ATP-dependent helicase domain. The N-terminus of these proteins is unique in that it encodes two caspase recruitment domains (CARDs), normally associated with cell death and inflammatory signaling pathways. Through numerous studies RIG-I and MDA5 have been found to play a key role in IFN induction following RNA virus infection. Through knockout analysis RIG-I has been shown to be the primary recognition receptor for majority of RNA viruses, while MDA5 is the major receptor for recognition of picornaviruses. Despite their specificities for various viral families, the two sensors often have overlapping roles and individually contribute to IFN production in response to infection. Both sensors appear to be activated by binding to dsRNA, with MDA5 being specific for long dsRNA molecules and RIG-I preferring dsRNA with an exposed 5 0 ppp group. Ubiquitous expression of RIG-I and MDA5 indicates that these sensors play a role in antiviral innate immunity in majority of tissues and cell types.