vIRF-1 regulation of mitophagy in HHV-8 biology

Johns Hopkins University, Baltimore MD

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Abstract

? DESCRIPTION (provided by applicant Successful virus replication is in large part achieved by the ability of viruses to counteract apoptosis and innate immune responses elicited by infection of host cells. Recent studies have demonstrated that mitochondria play a central role in anti-viral signaling pathways. Thus, a deeper understanding of how viral gene products regulate mitochondria during virus infection is essential to decipher viral mechanisms of immune evasion and cell survival. For human herpesvirus 8 (HHV-8), we previously showed that viral interferon regulatory factor 1 (vIRF-1) inhibits cytochrome c release induced by the pro-apoptotic BH3-only proteins (BOPs) Bim and Bid and localizes to mitochondria, we now know that vIRF-1 targets mitochondrial detergent resistant membrane (mitoDRM) fractions through its amino (N)-terminal proline-rich domain (PD; amino acids 1-75). However, the precise role of mitochondria-targeted vIRF-1 remains largely unknown. Here, we propose that vIRF-1 is a novel viral mitophagy receptor activated by mitochondrial dysfunction occurring during HHV-8 productive replication. Our preliminary studies indicate that mitochondrial content is reduced in vIRF-1-positive primary effusion lymphoma (PEL) cells that are undergoing lytic replication. In addition, vIRF-1 meets at least three criteria of a mitophagy receptor: localization to mitochondria, possession of an Atg8 family-interacting motif (AIM), and interaction with an Atg8 protein, GEC1/GABARAPL1, upon mitochondrial damage. On the other hand, vIRF-1 in mitoDRM was subject to caspase-mediated proteolysis during HHV-8 replication, and the cleavage of vIRF-1 was also induced by treatment with mitochondrial damaging drugs. These results suggest that HHV-8 productive replication may result in mitochondrial damage, which in turn activates caspases that leads to vIRF-1 activation of mitophagy. To determine the precise role of vIRF-1 in mitophagy induced during HHV-8 productive replication, this proposal focuses on: 1) identifying the molecular mechanisms by which vIRF-1 induces mitophagy during HHV-8 replication, 2) elucidating the functional significance of proteolysis of vIRF-1 in relation to mitophagy, and 3) assessing the biological significance of vIRF-1-mediated mitophagy in HHV-8 productive replication. Taken together, this proposal will provide a novel paradigm of virus-host interaction and a molecular basis for development of future antiviral agents.