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

Brisse, Morgan; Ly, Hinh

RIG-I and MDA5 additionally interact with different cellular co-factors, contributing to their differential regulations of function. RIG-I is well-known for being potentiated by proteins that also bind dsRNA, such as (PACT) (303, 304) , which was first discovered as a protein activator of PKR, the serine/threonineprotein kinase 1 (TBK1) (305) (306) (307) (308) (309) and the oligoadenylate synthetase L (OASL) (310) . PACT in particular has some functional similarities to RIG-I, as they each contain three distinct RNA binding domains (311) and interact with many of the same cellular co-factors, such as PKR (312) and Dicer (312, 313) . Because of the important role of PACT in augmenting RIG-I function, it is a prime target for inhibition of RIG-I signaling by several viral proteins from diverse families of viruses (314) (315) (316) , the molecular mechanisms of PACT inhibition by these viral proteins can vary and still need to be characterized in detail in future studies. Similarly, the host ribonucleoprotein RAVER1 can increase affinity of MDA5 for dsRNA (317) , and the zinc-finger protein ZCCHC3 has recently been found do so for both RIG-I and MDA5 (125) in similar mechanisms to the other known RNA-binding proteins. On the contrary, the human hemoglobin subunit beta (HB) has recently been suggested to decrease MDA5 signaling by competing for long dsRNA, while HB can enhance RIG-I signaling by increasing K63 ubiquitination on RIG-I (318) .