Post-Translational Events Underlying the KSHV vGPCR Pathogenesis

描述（由申请人提供）：vGPCR发病机制背后的翻译后事件，如卡波西肉瘤（KS）相关疱疹病毒（KSHV）等人γ疱疹病毒通常与免疫缺陷病毒-1感染相关，并在患者中诱导肿瘤。除了潜在蛋白外，KSHV裂解蛋白已被证明具有致瘤性或促生长活性，这表明裂解复制可能有助于KS和其他KSHV相关恶性肿瘤的疾病进展。一个有趣的例子是kshv编码的G蛋白偶联受体（vGPCR）。虽然vGPCR的致瘤性和下游信号事件已被更好地定义，但vGPCR是如何调控的尚不清楚。事实上，连续表达组成型活性gpcr（如vGPCR或视网膜视紫红质）可诱导哺乳动物细胞死亡，这提高了KSHV进化出控制vGPCR表达和活性的机制的可能性。我们的初步研究发现K7膜蛋白与vGPCR相互作用并诱导其蛋白酶体降解。此外，K7在内质网中保留了vGPCR并增加了vGPCR的泛素化。我们假设K7诱导内质网相关的vGPCR降解，并作为vGPCR肿瘤发生的负调节因子。我们的研究旨在阐明K7在引导vGPCR进入er相关降解中的分子作用。我们将采用遗传和生化分析来确定细胞因素，并表征它们在k7诱导的vGPCR降解中的作用。这些实验不仅将阐明vGPCR的细胞内调控，而且将揭示潜在靶向抗病毒治疗的细胞分子。公共卫生相关性：人类疱疹病毒，如卡波西肉瘤相关疱疹病毒（KSHV）在免疫缺陷患者中诱导肿瘤。KSHV有多种能够促进肿瘤形成的基因产物。本研究旨在研究其中一种病毒蛋白，KSHV G蛋白偶联受体，是如何在翻译后水平受到调控的。

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.