Post-Translational Events Underlying the KSHV vGPCR Pathogenesis

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DESCRIPTION (provided by applicant): Post-translational events underlying the pathogenesis of vGPCR Human gamma herpesviruses such as Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) are often associated with infection of immunodeficiency virus-1 and induce tumor in patients. In addition to latent proteins, KSHV lytic proteins have been demonstrated to possess tumorigenic or growth-promoting activities, indicating that lytic replication may contribute to the disease progression of KS and other KSHV-associated malignancies. One intriguing example is the KSHV-encoded G protein-coupled receptor (vGPCR). Although tumorigenicity and signaling events downstream of vGPCR are better defined, it is not clear how vGPCR is regulated. In fact, continuous expression of constitutively active GPCRs (e.g., vGPCR or retinal rhodopsin) induced cell death in mammalian cells, raising the possibility that KSHV has evolved mechanisms to control vGPCR expression and activity. Our preliminary study discovered that the K7 membrane protein interacts with vGPCR and induces its proteasome degradation. Furthermore, K7 retains vGPCR in the ER and increases vGPCR ubiquitination. We hypothesize that K7 induces the ER- associated degradation of vGPCR and functions as a negative regulator for vGPCR tumorigenesis. Our study proposes to elucidate the molecular action of K7 in routing vGPCR to the ER-associated degradation. We will employ both genetic and biochemical assays to identify cellular factors and characterize their roles in K7-induced vGPCR degradation. These experiments not only will elucidate the intracellular regulation of vGPCR, but also will reveal cellular molecules that can be potentially targeted for anti- viral therapy. PUBLIC HEALTH RELEVANCE: Human herpesviruses such as Kaposi's sarcoma-associated herpesvirus (KSHV) induce tumor in patients under conditions of immunodeficiency. KSHV has various gene products that are capable of promoting tumor formation. This study proposes to investigate how one of these viral proteins, the KSHV G protein-coupled receptor, is regulated at the post-translational level.