"DHX15: A novel regulator of innate antiviral response during RNA virus infection"
Retinoic acid inducible gene-I (RIG-I) and melanoma-differentiation-associated gene 5 (MDA5) are cytoplasmic pathogen recognition receptors. They are expressed in mammalian cells and serve an essential role in the recognition of RNA viruses and in induction of innate immune defenses against infection. Binding of viral RNA to RIG-I leads to downstream signaling through the MAVS adaptor protein. These processes drive the activation of transcription factors resulting in the production of type I interferons, proinflammatory cytokines, and the expression of innate immune genes that suppress virus infections. RIG-I signaling is considered to occur through interaction with undefined cofactors that serve regulatory roles in innate immunity. I have therefore applied a proteomic approach to identify RIG-I-binding proteins and possible cofactors of RIG-I signaling in human cells. I have identified a DEAD-box RNA helicase, DHX15 as a RIG-I binding protein. Preliminary studies show that cells lacking DHX15 are defective in RIG-I signaling, do not express innate immune genes in response to RNA virus infection , and are thus increasingly permissive to virus infection. I hypothesize that DHX15 is a regulator of RIG-I signaling and is an essential component of the RIG-I-MAVS signalosome complex with a role in limiting RNA virus infections. THe proposed studies will investigate this hypothesis to define the role of DHX15 and RIG-I interaction in innate antiviral immunity. Results from these studies will reveal novel mechanisms of innate immune signaling against RNA virus infection.