TMEM166/EVA1A interacts with ATG16L1 and induces autophagosome formation and cell death.
TMEM166/EVA1A interacts with ATG16L1 and induces autophagosome formation and cell death.
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TMEM166/EVA1A 与 ATG16L1 相互作用并诱导自噬体形成和细胞死亡
DOI：
10.1038/cddis.2016.230
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发表时间：
2016-08-04
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
自噬体的形成是由ATG蛋白的有序作用控制的。然而，这些蛋白是如何被招募到自噬膜上的仍不清楚。在这项研究中，我们提供了一系列证据，证实EVA1A (eva-1同源物a)/TMEM166（跨膜蛋白166）与自噬体膜发育有关。这一概念是基于与ZFYVE1、ATG9、LC3B、ATG16L1、ATG5、STX17、RAB7和LAMP1共定位的点状EVA1A结构，它们代表了自噬过程的不同阶段。这是自噬体形成所必需的，因为这种表型在Eva1a沉默细胞和Eva1a KO mef中显著降低。eva1a诱导的自噬不依赖于BECN1-PIK3C3（磷脂酰肌醇3-激酶，催化亚基3）复合物，但需要ATG7活性和ATG12-ATG5 /ATG16L1复合物。本研究提出了EVA1A通过其c -末端与ATG16L1的WD重复序列相互作用，促进ATG12-ATG5 /ATG16L1复合体向自噬膜募集并促进自噬体形成的分子机制。我们还发现，自噬和凋亡机制都有助于eva1a诱导的细胞死亡，而抑制自噬和凋亡可减轻eva1a诱导的细胞死亡。总的来说，这些发现为我们理解EVA1A在自噬和程序性细胞死亡中所涉及的途径提供了一个全面的视角。
The formation of the autophagosome is controlled by an orderly action of ATG proteins. However, how these proteins are recruited to autophagic membranes remain poorly clarified. In this study, we have provided a line of evidence confirming that EVA1A (eva-1 homolog A)/TMEM166 (transmembrane protein 166) is associated with autophagosomal membrane development. This notion is based on dotted EVA1A structures that colocalize with ZFYVE1, ATG9, LC3B, ATG16L1, ATG5, STX17, RAB7 and LAMP1, which represent different stages of the autophagic process. It is required for autophagosome formation as this phenotype was significantly decreased in EVA1A-silenced cells and Eva1a KO MEFs. EVA1A-induced autophagy is independent of the BECN1-PIK3C3 (phosphatidylinositol 3-kinase, catalytic subunit type 3) complex but requires ATG7 activity and the ATG12–ATG5/ATG16L1 complex. Here, we present a molecular mechanism by which EVA1A interacts with the WD repeats of ATG16L1 through its C-terminal and promotes ATG12–ATG5/ATG16L1 complex recruitment to the autophagic membrane and enhances the formation of the autophagosome. We also found that both autophagic and apoptotic mechanisms contributed to EVA1A-induced cell death while inhibition of autophagy and apoptosis attenuated EVA1A-induced cell death. Overall, these findings provide a comprehensive view to our understanding of the pathways involved in the role of EVA1A in autophagy and programmed cell death.
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