Formation and release of arrestin domain-containing protein 1-mediated microvesicles (ARMMs) at plasma membrane by recruitment of TSG101 protein
Formation and release of arrestin domain-containing protein 1-mediated microvesicles (ARMMs) at plasma membrane by recruitment of TSG101 protein
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DOI：
10.1073/pnas.1200448109
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发表时间：
2012-03-13
影响因子：
11.1
通讯作者：
Lu, Quan
中科院分区：
文献类型：
--
作者：
Nabhan, Joseph F.;Hu, Ruoxi;Lu, Quan
哺乳动物细胞能够在细胞外递送多种类型的膜囊。晚期内体的界膜可以与质膜融合，导致最初包含在内体中的多泡体（MVB）作为外泌体释放到细胞外。出芽病毒利用TSG101蛋白和用于MVB形成的转运所需的内体分选复合物（ESCRT）机制来介导病毒颗粒从宿主细胞中流出。在这里，我们报告了一个病毒独立的细胞过程的发现，产生微泡，是不同于外来体，其中，像出芽病毒，是由直接质膜出芽。这种出芽是由TSG101与辅助蛋白的四肽PSAP基序的特异性相互作用驱动的，所述辅助蛋白是含有抑制蛋白结构域的蛋白1（ARRDC1），我们显示其通过其抑制蛋白结构域定位于质膜。这种相互作用导致TSG101从内体重新定位到质膜，并介导含有TSG101、ARRDC1和其他细胞蛋白的微泡的释放。与来源于MVB的外泌体不同，ARRDC1介导的微囊泡（ARDCs）缺乏已知的晚期内体标记物。ARRDC1的形成需要VPS4 ATP酶，并通过E3连接酶WWP2增强，WWP2与ARRDC1相互作用并泛素化ARRDC1。在共培养的细胞中观察到ARRDC1蛋白被释放到ARM1中，表明ARM1在细胞间通讯中的作用。我们的研究结果揭示了一种内在的细胞机制，导致微泡从质膜直接出芽，为ESCRT蛋白在出芽病毒释放中的进化招募提供了一个正式的范例。
Mammalian cells are capable of delivering multiple types of membrane capsules extracellularly. The limiting membrane of late endosomes can fuse with the plasma membrane, leading to the extracellular release of multivesicular bodies (MVBs), initially contained within the endosomes, as exosomes. Budding viruses exploit the TSG101 protein and endosomal sorting complex required for transport (ESCRT) machinery used for MVB formation to mediate the egress of viral particles from host cells. Here we report the discovery of a virus-independent cellular process that generates microvesicles that are distinct from exosomes and which, like budding viruses, are produced by direct plasma membrane budding. Such budding is driven by a specific interaction of TSG101 with a tetrapeptide PSAP motif of an accessory protein, arrestin domain-containing protein 1 (ARRDC1), which we show is localized to the plasma membrane through its arrestin domain. This interaction results in relocation of TSG101 from endosomes to the plasma membrane and mediates the release of microvesicles that contain TSG101, ARRDC1, and other cellular proteins. Unlike exosomes, which are derived from MVBs, ARRDC1-mediated microvesicles (ARMMs) lack known late endosomal markers. ARMMs formation requires VPS4 ATPase and is enhanced by the E3 ligase WWP2, which interacts with and ubiquitinates ARRDC1. ARRDC1 protein discharged into ARMMs was observed in co-cultured cells, suggesting a role for ARMMs in intercellular communication. Our findings reveal an intrinsic cellular mechanism that results in direct budding of microvesicles from the plasma membrane, providing a formal paradigm for the evolutionary recruitment of ESCRT proteins in the release of budding viruses.