Novel functions of Kaposi’s sarcoma herpesvirus viral FLICE inhibitory protein

Abstract

KSHV vFLIP is a potent activator of NFκB signaling and an inhibitor of apoptosis and autophagy. Inhibition of vFLIP function and NFκB signaling promotes viral reactivation. Here we provide evidence for a novel function of vFLIP in promoting NFߢB signaling through inhibition of the DUB activity of the negative regulator, A20. We demonstrate interaction of vFLIP with the Itch/A20 ubiquitin editing complex. We have identified a SUMO interaction motif in vFLIP that is required for NFκB activation. We observed a decrease in vFLIP induced NFκB when the SIM in vFLIP was mutated. Small molecule inhibition of SUMOylation resulted in a dose dependent increase lytic reactivation and virus production. Our results suggest a role for SUMO in mediating vFLIP function and provide evidence for vFLIP modulation of the negative regulation of NFκB signaling by A20. Our results provide further insight into the function of vFLIP and SUMO in the regulation of NFκB signaling and the latent lytic transition.