Post-Translational Events Underlying the KSHV vGPCR Pathogenesis

摘要/摘要 标题：vGPCR发病机制的翻译后事件 与卡波西肉瘤(KS)相关的人类伽玛疱疹病毒 疱疹病毒(KSHV)通常与免疫缺陷病毒-1和 在患者中诱发肿瘤。除潜伏蛋白外，KSHV裂解蛋白已被 被证明具有致瘤或促进生长的活性，表明溶血 复制可能有助于KS和其他KSHV相关疾病的进展 恶性肿瘤。一个有趣的例子是KSHV编码的G蛋白偶联受体 (VGPCR)。尽管vGPCR下游的致瘤性和信号事件 更好的定义是，尚不清楚vGPCR是如何受到监管的。事实上，不断表达的 成分活性GPCRs(如vGPCR或视网膜视紫红质)诱导的细胞死亡 哺乳动物细胞，增加了KSHV进化控制机制的可能性 VGPCR的表达和活性。 我们的初步研究发现，K7膜蛋白与 VGPCR并诱导其蛋白酶体降解。此外，K7将vGPCR保留在 ER和增加vGPCR泛素化。我们假设K7诱导ER- VGPCR的联合降解及其负性调节作用 肿瘤发生学。我们的研究建议阐明K7在路由中的分子作用 VGPCR对内质网相关的降解。我们将同时使用遗传和生化技术 鉴定细胞因子及其在K7诱导的vGPCR中的作用的方法 退化。这些实验不仅将阐明细胞内的调节 VGPCR，但也将揭示潜在的抗靶向细胞分子 病毒疗法。

Abstract/Summary Title: 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.