Post-Translational Events Underlying the KSHV vGPCR Pathogenesis

摘要/概要 标题：vGPCR发病机制的翻译后事件 人γ疱疹病毒，如卡波西肉瘤（KS）相关 疱疹病毒（KSHV）通常与免疫缺陷病毒-1感染有关， 诱发患者肿瘤。除了潜伏蛋白外，KSHV裂解蛋白也已被发现。 证明具有致瘤或促生长活性，表明裂解 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传导事件是不可避免的， 更好地定义，尚不清楚vGPCR是如何调节的。事实上，连续表达 组成型活性GPCR（例如，vGPCR或视网膜视紫红质）诱导的细胞死亡。 哺乳动物细胞，提高了KSHV已经进化出控制机制的可能性。 vGPCR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在细胞中保留vGPCR。 ER和增加vGPCR泛素化。我们假设K7诱导ER- vGPCR的相关降解，并作为vGPCR的负调节因子发挥作用 肿瘤发生我们的研究旨在阐明K7在路由中的分子作用 vGPCR对ER相关降解的影响。我们将使用遗传学和生物化学 鉴定细胞因子并表征其在K7诱导的vGPCR中的作用的试验 降解这些实验不仅将阐明细胞内调节 vGPCR，但也将揭示细胞分子，可以潜在地针对抗- 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.