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

Brisse, Morgan; Ly, Hinh

There is also increasing evidence for other RNA-sensing DExD/H helicases serving important roles in anti-pathogen immune sensing, which have recently been reviewed elsewhere (187) . Some RNA helicase (DDX) proteins appear to serve as complex proteins upon interacting with viral RNA. DDX3 is a well-known example, being suspected of being a transcription factor for IFN-β (378), associating with spliceosomes and the stress-induced p-bodies to influence mRNA splicing and decay, respectively (322, 378) , and interacting with the MAVS complex during viral infection conditions (378, 379) . In particular, DDX3 associating with MAVS has been found to be important for anti-viral control against several viruses (378) (379) (380) , and since the two DDX3 homologs are found on the X and Y chromosomes, they may contribute to immunological differences between genders (381). This is a repeated theme, as DHX9 (382), DHX15 (383) , and a complex consisting of DDX1/DDX21/DHX36 (384) have also been found to associate with the MAVS complex to enhance IFN1 signaling, while DHX33 interacts with MAVS independently of viral infection (385) . DDX proteins can also activate other proteins in the IRF pathway. Multiple DDX proteins can interact with IKKε, with DDX3 being phosphorylated by IKKε to induce IRF3 interaction with the TBK1-IKKε complex (378) , and DDX19 blocking this interaction to inhibit IFN1 signaling (386) . Similar control mechanisms have been demonstrated for DDX3 interacting with viral proteins. For example, DDX3 has recently been found to associate with arenaviral NPs to increase viral RNA synthesis and IFN1 expression (387) . Additionally, the NP of the 1918 H1N1 IAV pandemic strain has been shown to target DDX3 for degradation as a potential mechanism of virulence (388) . DHX15 (389) and DHX33 have also been found to activate NFκB and MAPK signaling pathways. Finally, DDX60 has been shown to act as a cofactor for RIG-I (390, 391) and DHX29 for MDA5 (392) . Taken altogether, these cellular proteins have likely evolved to regulate RIG-I and MDA5 signaling from their common DExD/H helicase predecessors.