文章：

HIV-1 p17变异的b细胞克隆活性是由 PAR1介导的EGF转激活驱动的

B-cell clonogenic activity of HIV-1 p17 variants is driven by PAR1-mediated EGF transactivation 

原文发布日期：2020-10-22 

英文摘要：

Combined antiretroviral therapy (cART) for HIV-1 dramatically slows disease progression among HIV+ individuals. Currently, lymphoma represents the main cause of death among HIV-1-infected patients. Detection of p17 variants (vp17s) endowed with B-cell clonogenic activity in HIV-1-seropositive patients with lymphoma suggests their possible role in lymphomagenesis. Here, we demonstrate that the clonogenic activity of vp17s is mediated by their binding to PAR1 and to PAR1-mediated EGFR transactivation through Gq protein. The entire vp17s-triggered clonogenic process is MMPs dependent. Moreover, phosphoproteomic and bioinformatic analysis highlighted the crucial role of EGFR/PI3K/Akt pathway in modulating several molecules promoting cancer progression, including RAC1, ABL1, p53, CDK1, NPM, Rb, PTP-1B, and STAT1. Finally, we show that a peptide (F1) corresponding to the vp17s functional epitope is sufficient to trigger the PAR1/EGFR/PI3K/Akt pathway and bind PAR1. Our findings suggest novel potential therapeutic targets to counteract vp17-driven lymphomagenesis in HIV+ patients. 

摘要翻译： 

联合抗逆转录病毒疗法（cART）可显著延缓HIV-1阳性患者的疾病进展。目前，淋巴瘤已成为HIV-1感染者的主要死亡原因。在HIV-1血清阳性淋巴瘤患者体内发现的具有B细胞克隆形成活性的p17变异体（vp17s），提示其可能在淋巴瘤发生中发挥作用。本研究证实vp17s的克隆形成活性是通过与PAR1结合，并经由Gq蛋白介导的EGFR反式激活实现的。整个vp17s触发的克隆形成过程依赖基质金属蛋白酶（MMPs）。磷酸化蛋白质组学和生物信息学分析进一步揭示EGFR/PI3K/Akt通路通过调控RAC1、ABL1、p53、CDK1、NPM、Rb、PTP-1B和STAT1等多种促癌分子发挥关键作用。最后，我们发现与vp17s功能表位对应的F1多肽足以激活PAR1/EGFR/PI3K/Akt通路并与PAR1结合。这些发现为对抗HIV阳性患者vp17驱动的淋巴瘤发生提供了新的潜在治疗靶点。

原文链接：

B-cell clonogenic activity of HIV-1 p17 variants is driven by PAR1-mediated EGF transactivation