TBC1D14 regulates autophagy via the TRAPP complex and ATG9 traffic.
TBC1D14 regulates autophagy via the TRAPP complex and ATG9 traffic.
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DOI：
10.15252/embj.201592695
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发表时间：
2016-02-01
期刊：
影响因子：
--
通讯作者：
Tooze SA
中科院分区：
文献类型：
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作者：
Lamb CA;Nühlen S;Judith D;Frith D;Snijders AP;Behrends C;Tooze SA
大自噬需要膜运输和重塑以形成自噬体并将其内容物递送至溶酶体进行降解。我们之前已经确定了含有TBC结构域的蛋白质TBC1D14作为自噬的负调节因子，控制从RAB 11阳性再循环内体传递膜以形成自噬体。在这项研究中，我们确定了TRAPP复合物，一种多亚基拴系复合物和RAB1的GEF，作为TBC1D14的相互作用物。TBC1D14通过N端103个氨基酸区域与TRAPP复合物结合，该区域的过表达抑制自噬和分泌运输。TRAPPC8是酵母自噬特异性TRAPP亚基的哺乳动物直向同源物，形成哺乳动物TRAPPIII样复合物的一部分，该复合物和TBC1D14都是RAB1激活所需的。TRAPPC8调节自噬和分泌运输，并且是TBC1D14结合TRAPPIII所需的。重要的是，TBC1D14和TRAPPIII独立于ULK1调节ATG9运输。我们提出了一个模型，其中TBC1D14和TRAPPIII调节从外周循环内体到早期高尔基体的组成性运输步骤，维持启动自噬所需的ATG9循环池。
Macroautophagy requires membrane trafficking and remodelling to form the autophagosome and deliver its contents to lysosomes for degradation. We have previously identified the TBC domain‐containing protein, TBC1D14, as a negative regulator of autophagy that controls delivery of membranes from RAB11‐positive recycling endosomes to forming autophagosomes. In this study, we identify the TRAPP complex, a multi‐subunit tethering complex and GEF for RAB1, as an interactor of TBC1D14. TBC1D14 binds to the TRAPP complex via an N‐terminal 103 amino acid region, and overexpression of this region inhibits both autophagy and secretory traffic. TRAPPC8, the mammalian orthologue of a yeast autophagy‐specific TRAPP subunit, forms part of a mammalian TRAPPIII‐like complex and both this complex and TBC1D14 are needed for RAB1 activation. TRAPPC8 modulates autophagy and secretory trafficking and is required for TBC1D14 to bind TRAPPIII. Importantly, TBC1D14 and TRAPPIII regulate ATG9 trafficking independently of ULK1. We propose a model whereby TBC1D14 and TRAPPIII regulate a constitutive trafficking step from peripheral recycling endosomes to the early Golgi, maintaining the cycling pool of ATG9 required for initiation of autophagy.