145: DHX15: A novel regulator of innate immune defense to RNA virus infections

Abstract

Retinoic acid inducible gene-I (RIG-I) is a cytoplasmic pathogen recognition receptor expressed in mammalian cells where it serves an essential role in the recognition of RNA viruses and to signal the induction of innate immune defenses. Binding of viral RNA by 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 infection. We have found that RIG-I signaling to MAVS is mediated through a complex assembly of signaling co-factors that play regulatory roles in innate immunity. We therefore applied a proteomic approach coupled with assessment of innate immune signaling function to define RIG-I co-factors. Among the RIG-I-binding proteins we identified the DEAD-box RNA helicase, DHX15. Human cell lines with knockdown of DHX15 are defective in RIG-I signaling, do not express innate immune genes in response to RNA virus infection, and are highly permissive to virus infection compared to control cells expressing DHX15. Biochemical studies reveal that DHX15 is a component of RLR pathway that facilitates RIG-I/MAVS interaction to promote innate immune signaling. Further structure/function and enzymatic studies of DHX15 will be presented.