Role of BAP1 in the biphasic life cycle of KSHV

/ ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic gammaherpesvirus with a biphasic life cycle consisting of a latent and lytic phase. KSHV is the etiological agent of several diseases and cancers including Kaposi's sarcoma and primary effusion lymphoma (PEL). Initial infection in oral epithelial cells supports the lytic phase, allowing KSHV to replicate and produce infectious virions. Spread from the oral cavity to B cells in lymph nodes results in latency establishment, characterized by repressed lytic genes imparted by heterochromatinization of the viral genome not seen in oral epithelial cells. As a result, the virus is able to evade immune detection and promote tumorigenesis primarily in immunocompromised hosts. We aim to identify host factors that are involved in promoting the KSHV life cycle so as to identify potential targets for therapeutic interventions. We have shown that the viral prolytic protein ORF45 interacts with lytic cycle-promoting host transcription factors FOXK1/2. Interestingly, we also discovered the presence of a functional motif on ORF45 that is known to be present in various host proteins including BRCA1-associated protein 1 (BAP1) and promotes their interaction with FOXK1/2. BAP1 acts as a tumor suppressor with its loss of function mutations implicated in a wide range of cancers which interrupt its normal cellular functions such as its deubiquitinase activity that antagonizes heterochromatin formation and its regulatory role in cell proliferation. Yet in virus-induced cancer contexts and during lytic viral infection, BAP1 remains uncharacterized. Our preliminary data reveals a contrasting, context-specific role of BAP1 during KSHV infection, with pro-lytic activity during lytic infection of oral epithelial cells but pro-latent functions during latency in PEL cells. Our goal is to dissect the mechanisms whereby BAP1 promotes KSHV lytic infection in oral epithelial cells, and maintains latency and regulates tumor proliferation in PEL. The goal is to provide future therapeutic considerations to reduce virus transmission in the oral cavity and prevent life-long persistent latency that leads to cancer burden. Project Number: 1F31DE035811-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Alessandro Leo | Institution: UNIVERSITY OF FLORIDA, GAINESVILLE, FL | Award Amount: $45,037 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F07C-H (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11315091