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Retinoic acid-inducible gene I (RIG-I) functions as a cytosolic pathogen recognition receptor by binding the pathogen associated molecular patterns (PAMPs) in viral RNA. The molecular signature for RIG-I recognition has been identified as 5′-triphosphate-containing short double stranded or poly-uridine RNA (5′pppRNA) structures found in RNA species that amass in the cytoplasm during virus infection. PAMP-mediated activation of RIG-I triggers many signaling cascades that mediates its effector functions in innate immunity and apoptosis. In the innate immune response to virus infection, RIG-I sets off both IRF3/7 and NF-κB signaling to induce type I interferon (IFN) and pro-inflammatory cytokine production respectively. PAMP-induced RIG-I activation can also induce apoptosis in cancer cells. Since PAMP RNA can act as the activator of RIG-I’s pro-apoptotic and innate immune functions, we hypothesized that the induction of these separate pathways is programmed through differential RIG-I-cofactor interactions. We have identified and characterized novel co-factors of RIG-I by using a systems proteomic approach. These co-factors serve to program apoptotic versus innate immune signaling actions through their interaction with RIG-I. These co-factors and their biologic functions will be presented.

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