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

Brisse, Morgan; Ly, Hinh

The RIG-I CARD domain interacts with MAVS to induce interferon signaling, so proteins that disrupt this interaction [as it has been proposed for the Atg5 and Atg12 autophagy proteins (59) ] can specifically inhibit RIG-I signaling. However, other cellular proteins, such as the complement protein gC1qR (327) and TARBP2 (328) that interact directly with MAVS, inhibit both RIG-I and MDA5. Lactate and hexokinase have also recently been found to inhibit RIG-I and MDA5 by interacting with MAVS, which may be significant in explaining the interplay between metabolism and immune signaling as glycolysis was found to be greatly decreased upon RLR signaling (329) . Likewise, cellular proteins, such as NLRC5 (330) that interacts with the RIG-I and MDA5 CARD domains have been shown to block interaction of both RIG-I and MDA5 with MAVS. Contrarily, DHX15 has been identified as a RIG-I cofactor that interacts with the RIG-I CARD domains and with PAMP (dsRNA), thereby increasing RIG-I ATPase activity (331) . Additionally, ADP-ribosylation factor proteins can block RIG-I and MDA5 from interacting with PAMPs and thereby inhibit their activation (332, 333) . Lastly, the green tea molecule EGCG has also been shown to inhibit the ATPase function of RIG-I (334) . The similarities and differences between RIG-I and MDA5 modulations and signaling are complex and will need to be elucidated further in future studies.