The Mitochondrial Anti-Viral Signaling Protein, MAVS: Overexpressed in Tumors, Interact with Caspase-8, VDAC1 and tBID to Regulate Apoptosis

The mitochondrial anti-viral signaling protein (MAVS) plays an important role in host defense against viral infection via coordinating the activation of NF-κB and interferon regulatory factors (IRF3 and IRF7). Recent studies suggest the involvement of MAVS in viral-induced apoptosis via its predicted interaction with the outer mitochondrial membrane protein VDAC1. VDAC1 is a dynamic regulator of global mitochondrial function in both health and disease. VDAC1 controls cellular energy production and metabolism by mediating the exchange of metabolites and ions between mitochondria and the rest of cell, thereby regulating cell survival. VDAC1 has also been proposed to function as a key player in apoptosis. We have found that MAVS is over-expressed in many cancer types, including lung and cervical cancers, chronic lymphocytic leukemia and others. This study aimed to explore the unclear function of MAVS in cancer. Using several approaches, we demonstrate the direct interaction of MAVS with VDAC1 and with the pro-apoptotic proteins caspase-8 and tBid. MAVS prevented the cleavage of Bid by caspase 8 to produce apoptosis inducer, tBid. We further demonstrate that MAVS offered protection against apoptosis as induced by various means, although this effect was most pronounced with TNF-α, acting via the extrinsic apoptotic pathway leading to caspase 8 activation and tBid formation that subsequently activates mitochondria-mediated apoptosis. These results suggest that MAVS acts as anti-apoptotic protein by interacting with caspase-8, VDAC1 or tBid to interfere with their pro-apoptotic activities. Furthermore, the findings presented here point to MAVS-VDAC1 and MAVS-tBid interactions as new targets for cancer therapy.