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

Brisse, Morgan; Ly, Hinh

One of the most significant ways viruses modulate RIG-I and MDA5 signaling is through their viral proteins (272) (Figure 6) . The respiratory syncytial virus (RSV) non-structural protein (NS2) protein and the Z matrix proteins of pathogenic arenaviruses interact with the RIG-I CARD domains to block its interaction with MAVS (273, 274) . The HSV1 deamidase UL37 specifically targets RIG-I through its helicase domain, abrogating its ability to bind to RNA (275) . The IAV polymerase components also interact directly with RIG-I (276), though their biological significance has yet to be determined as they don't significantly affect IFN1 production. On the other hand, RNA binding appears to be an important bridge between the interaction of RIG-I with other viral proteins, as the nucleoproteins (NPs) of IAV (276) and arenaviruses (277, 278) both interact with RIG-I through viral RNA. The NS1 protein of rotaviruses targets RIG-I for degradation that is independent of proteasomes (279) . The V protein of paramyxoviruses inhibits MDA5 (40) by targeting a unique feature of the ATP binding pocket in MDA5 (280) and by inhibiting MDA5 CARD dephosphorylation (93) , but can also inhibit RIG-I by interacting with the CARD domain to prevent its ubiquitination by TRIM25 (281) . Finally, the US11 protein of HSV1 (282) and the arenaviral Z matrix proteins (274) directly interact with and inhibit RIG-I and MDA5 in a similar fashion. There are also many other viral proteins that can regulate proteins in the RIG-I and MDA5 pathways, which have been discussed in detail elsewhere (44, 53, 59, 96, 257, 283) .