Comparative Structure and Function Analysis of the RIG-I-Like Receptors: RIG-I and MDA5

Brisse, Morgan; Ly, Hinh

RIG-I and MDA5 appear to differentially induce IFN1 in response to different viral pathogens (17), with RIG-I generally responding most potently to negative-strand RNA viruses, such as influenza viruses (18, 19) , bunyaviruses (20, 21), filoviruses (22), and rhabdoviruses (18, 23) as well as the positive-stranded Japanese encephalitis virus (18), while MDA5 is activated during infection by positive-strand picornaviruses (18, 24, 25) and arteriviruses (26, 27) as well as by hepatitis D virus (28), Kaposi's sarcoma-associated herpesvirus (KSHV) (29). RIG-I and MDA5 may also play a role in recognizing non-viral pathogens, as MDA5 has been found to respond to malaria (30) (Figure 2) . Neither are individually critical in reovirus (24) and in dengue virus infection (24, 31) but the presence of either in combination with Toll-like receptor 3 (TLR3) is critical to have effective anti-viral repsonses (32). Each serves an additive role during West Nile virus infection (33), which is likely mediated by the production of multiple PAMP species in the infected cells (34). Indeed, RIG-I and MDA5 have also been shown to recognize different sections of the same viral genome due to their differing preferences for RNA binding (35), illustrating how RIG-I and MDA5 can act both independently and synergistically. This has also been shown functionally in viruses where both RIG-I and MDA5 have been found to be essential to induce the necessary levels of IFNβ signaling for antiviral control against paramyxovirus (18, 36-38) and rotavirus infections (39).