NFAT activation in kGPCR tumorigenesis

摘要 疱疹病毒在人类中普遍存在，它们与多种恶性肿瘤有关。人类 卡波西肉瘤相关疱疹病毒(KSHV)和爱泼斯坦-巴尔病毒与肿瘤相关 免疫受损患者的淋巴样来源、上皮来源和内皮来源。这些人类的能力 导致肿瘤形成的病原体很大程度上归因于病毒基因组中包含的癌基因(S)。 当在细胞中表达时，致癌病毒多肽触发细胞信号级联反应，最终导致 促进细胞增殖和存活。这种病毒信号分子之一是KSHV G蛋白偶联 受体(KGPCR)。 KGPCR是一种具有七个跨膜结构的蛋白质，通过质膜传递信号。尽管是一名 作为人IL-8受体的功能同源物，kGPCR在结构上具有独立于配体结合的活性。 KGPCR下游的一个关键信号通路是活化T细胞核因子(NFAT)的激活。 然而，kGPCRa如何调节NFAT的激活以及NFAT在kGPCRa肿瘤发生中的作用尚不清楚 很好理解。特别是，kGPCR-NFAT-趋化因子电路为前馈结果提供燃料，这意味着 消极监管机制的存在。在这项研究中，我们建议通过以下方式来描述这种机制 它探索了一种激酶和代谢酶来负向调节和调节NFAT的激活， 从而促进肿瘤的发生。我们将使用药物来过度激活NFAT和TWART KGPCR型肿瘤形成。总体而言，我们的工作将破译信号迷宫，并开发一种新的抗病毒和 针对致癌GPCRs的抗肿瘤策略，指导我们寻找治疗KSHV相关的新方法 恶性肿瘤和其他与NFAT激活相关的疾病。

Abstract Herpesviruses are ubiquitous in humans and they have been implicated in diverse malignancies. Human Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus are associated with tumors of lymphoid, epithelial, and endothelial origin in immuno-compromised patients. The ability of these human pathogens to induce tumor formation is largely attributable to oncogene(s) that the viral genome contains. When expressed in cells, oncogenic viral polypeptides trigger cellular signaling cascades that culminate in promoting cell proliferation and survival. One of such viral signaling molecules is the KSHV G protein-coupled receptor (kGPCR). kGPCR is a seven-transmembrane protein that transmits signal across the plasma membrane. Despite being a functional homolog of the human IL-8 receptor, kGPCR is constitutively active independent of ligand binding. One key signaling pathway downstream kGPCR is the activation of nuclear factor of activated T cells (NFAT). However, how kGPCR regulates NFAT activation and the roles of NFAT in kGPCR tumorigenesis remain not well understood. In particular, the kGPCR-NFAT-chemokine circuitry fuels a feed-forward outcome, implying the existence of negative regulatory mechanisms. In this study, we propose to delineate the mechanism by which kGPCR explores a kinase and a metabolic enzyme to negatively regulate and tune NFAT activation, thereby promoting tumorigenesis. We will employ pharmacological agents to hyper-activate NFAT and thwart kGPCR tumor formation. Overall, our work will decipher the signaling labyrinth and develop a new antiviral and antitumor strategy targeting oncogenic GPCRs, instructing us on new means to treat KSHV-associated malignancies and other diseases related to NFAT activation.