ID: 104: Opposing roles of two dsRNA binding proteins PACT and TRBP on RIG-I induced interferon production

An integral aspect of innate immunity is the ability to detect non-self molecules to initiate antiviral signaling via pattern recognition receptors (PRRs). One such receptor is the RNA helicase RIG-I, which has the ability to detect and be activated by 5’triphosphate uncapped double stranded RNA (dsRNA) as well as the viral mimic dsRNA polyI:C. Once activated, RIG-I’s CARD domains oligomerize and initiate downstream MAVS signaling ultimately inducing interferon (IFN) production. Another dsRNA binding protein PACT, originally identified as the cellular protein activator of PKR, has recently been shown to stimulate RIG-I signaling in response to polyI:C treatment, in part by stimulating RIG-I’s ATPase and helicase activities and resulting in an enhanced induction of IFN. TRBP (TAR-RNA-binding protein), which is about 45% homologous to PACT is known to inhibit PKR signaling by sequestration of PKR and its’ activators, dsRNA and PACT. Despite the domain homology and similar structure of PACT and TRBP, the role of TRBP is yet to be explored in RIG-I like receptor (RLR) signaling. This work focuses on the effect of TRBP on RIG-I signaling and IFN production. Our results indicate that TRBP acts as an inhibitor of RIG-I signaling in a PACT- and PKR-independent manner. This work has major implications on viral susceptibility, disease progression, and antiviral immunity as it demonstrates the regulatory interplay between two dsRNA binding proteins PACT and TRBP on RIG-I mediated IFN production.