A Rab3a-dependent complex essential for lysosome positioning and plasma membrane repair.
A Rab3a-dependent complex essential for lysosome positioning and plasma membrane repair.
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DOI：
10.1083/jcb.201511093
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发表时间：
2016-06-20
期刊：
影响因子：
--
通讯作者：
Vieira OV
中科院分区：
文献类型：
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作者：
Encarnação M;Espada L;Escrevente C;Mateus D;Ramalho J;Michelet X;Santarino I;Hsu VW;Brenner MB;Barral DC;Vieira OV
恩卡纳昂等人。结果表明，Rab3a与其新发现的效应物NMHC IIA一起，介导外周溶酶体在非分泌细胞中的定位，从而促进溶酶体的胞吐和质膜修复。溶酶体胞吐作用在质膜(PM)破裂的再密封中起主要作用。这个过程包括两个连续的步骤。首先，溶酶体被招募到细胞的外围，然后与受损的PM融合然而，涉及溶酶体胞吐和PM修复(PMR)的转运分子机制却知之甚少。我们对人类RAB家族进行了系统的筛选，以确定溶酶体胞吐和PMR所需的RAB。Rab3a部分定位于外周溶酶体，是最强劲的热门之一。沉默Rab3a或其效应物突触素样蛋白4a(SLP4-a)会导致溶酶体崩溃到核周区域，并抑制PMR。重要的是，我们还发现了一个新的Rab3效应器，非肌肉肌球蛋白重链IIA，它是Rab3a和SLP4-a形成的复合体的一部分，负责溶酶体在细胞外围的定位和溶酶体的胞吐。
Encarnação et al. show that Rab3a, together with its newly identified effector NMHC IIA, mediates the positioning of peripheral lysosomes in nonsecretory cells, thereby promoting lysosome exocytosis and plasma membrane repair. Lysosome exocytosis plays a major role in resealing plasma membrane (PM) disruptions. This process involves two sequential steps. First, lysosomes are recruited to the periphery of the cell and then fuse with the damaged PM. However, the trafficking molecular machinery involved in lysosome exocytosis and PM repair (PMR) is poorly understood. We performed a systematic screen of the human Rab family to identify Rabs required for lysosome exocytosis and PMR. Rab3a, which partially localizes to peripheral lysosomes, was one of the most robust hits. Silencing of Rab3a or its effector, synaptotagmin-like protein 4a (Slp4-a), leads to the collapse of lysosomes to the perinuclear region and inhibition of PMR. Importantly, we have also identified a new Rab3 effector, nonmuscle myosin heavy chain IIA, as part of the complex formed by Rab3a and Slp4-a that is responsible for lysosome positioning at the cell periphery and lysosome exocytosis.