Inhibition of A20 deubiquitinase activity by KSHV vFLIP: A SUMO dependent mechanism?
KSHV viral FLICE inhibitory protein (vFLIP) is a potent activator of NF-{kappa}B signaling and an inhibitor of apoptosis and autophagy. Inhibition of vFLIP function and NF-{kappa}B signaling promotes lytic reactivation. Here we provide evidence for a novel function of vFLIP in promoting NF{kappa}B 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 NF-{kappa}B activation. Mutation of the SIM in BAC16 resulted in increased spontaneous RTA expression and loss of spindle cell morphology. Our results suggest a role for SUMO in mediating vFLIP function and provide evidence for vFLIP modulation of the negative regulation of NF-{kappa}B signaling by A20. Our results provide further insight into the function of vFLIP and SUMO in the regulation of NF-{kappa}B signaling and the latent lytic transition.