Department of Medicine, University of California, San Francisco, 600 16th Street, San Francisco, CA 94158, USA; UCSF Helen Diller Comprehensive Cancer Center, University of California, San Francisco, 600 16th Street, San Francisco, CA 94158, USA; Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.
Department of Physiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.
Cell Rep. 2021 Aug 3;36(5):109491. doi: 10.1016/j.celrep.2021.109491.
The exocyst is an evolutionarily conserved protein complex that regulates vesicular trafficking and scaffolds signal transduction. Key upstream components of the exocyst include monomeric RAL GTPases, which help mount cell-autonomous responses to trophic and immunogenic signals. Here, we present a quantitative proteomics-based characterization of dynamic and signal-dependent exocyst protein interactomes. Under viral infection, an Exo84 exocyst subcomplex assembles the immune kinase Protein Kinase R (PKR) together with the Hippo kinase Macrophage Stimulating 1 (MST1). PKR phosphorylates MST1 to activate Hippo signaling and inactivate Yes Associated Protein 1 (YAP1). By contrast, a Sec5 exocyst subcomplex recruits another immune kinase, TANK binding kinase 1 (TBK1), which interacted with and activated mammalian target of rapamycin (mTOR). RALB was necessary and sufficient for induction of Hippo and mTOR signaling through parallel exocyst subcomplex engagement, supporting the cellular response to virus infection and oncogenic signaling. This study highlights RALB-exocyst signaling subcomplexes as mechanisms for the integrated engagement of Hippo and mTOR signaling in cells challenged by viral pathogens or oncogenic signaling.
外被体(exocyst)是一种进化上保守的蛋白质复合物，可调节囊泡运输并支架信号转导。外被体的关键上游组件包括单体 RAL GTPases，它有助于启动细胞自主对营养和免疫信号的反应。在这里，我们基于定量蛋白质组学对动态和信号依赖性外被体蛋白相互作用组进行了描述。在病毒感染下，一个 Exo84 外被体亚基将免疫激酶蛋白激酶 R (PKR)与 Hippo 激酶巨噬细胞刺激素 1 (MST1)组装在一起。PKR 磷酸化 MST1 以激活 Hippo 信号并使 Yes 相关蛋白 1 (YAP1)失活。相比之下，Sec5 外被体亚基招募另一种免疫激酶 Tank 结合激酶 1 (TBK1)，它与哺乳动物雷帕霉素靶蛋白 (mTOR)相互作用并激活 mTOR。RALB 通过平行外被体亚基的参与对于诱导 Hippo 和 mTOR 信号是必需和充分的，这支持了细胞对病毒感染和致癌信号的反应。本研究强调了 RALB-外被体信号亚基作为 Hippo 和 mTOR 信号在受病毒病原体或致癌信号挑战的细胞中整合的机制。
