The Atg1-kinase complex tethers Atg9-vesicles to initiate autophagy.
The Atg1-kinase complex tethers Atg9-vesicles to initiate autophagy.
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DOI：
10.1038/ncomms10338
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发表时间：
2016-01-12
影响因子：
16.6
通讯作者：
Wollert T
中科院分区：
文献类型：
--
作者：
Rao Y;Perna MG;Hofmann B;Beier V;Wollert T
自噬体是双膜囊泡，可隔离细胞质物质以供溶酶体降解。它们的生物发生是通过将Atg 9囊泡募集到吞噬细胞组装位点来启动的。这一过程依赖于Atg 1-激酶复合物的调节激活。然而，潜在的分子机制仍不清楚。在这里，我们从体外纯化的成分中重建了自噬的早期步骤。我们发现，从其细胞质亚复合物的组装，Atg 1-激酶复合物被激活，使其能够招募和拴Atg 9-囊泡。支架蛋白Atg 17通过特异性识别膜蛋白Atg 9将Atg 1-激酶复合物靶向自噬膜。这种相互作用被两个调节亚基Atg 31和Atg 29抑制。参与的Atg 1-Atg 13亚复合物恢复Atg 9结合和膜拴系活性的Atg 17。我们的数据有助于解开控制Atg 17介导的Atg 9囊泡束缚的机制，为理解自噬体生物发生的启动提供分子基础。 自噬体的生物发生是由Atg 9-囊泡的吞噬细胞组装网站的招聘。在这里，Rao等人使用体外重建系统来描述Atg 1-激酶复合物从其组成部分激活募集和束缚Atg 9-囊泡的机制。
Autophagosomes are double-membrane vesicles that sequester cytoplasmic material for lysosomal degradation. Their biogenesis is initiated by recruitment of Atg9-vesicles to the phagophore assembly site. This process depends on the regulated activation of the Atg1–kinase complex. However, the underlying molecular mechanism remains unclear. Here we reconstitute this early step in autophagy from purified components in vitro. We find that on assembly from its cytoplasmic subcomplexes, the Atg1–kinase complex becomes activated, enabling it to recruit and tether Atg9-vesicles. The scaffolding protein Atg17 targets the Atg1–kinase complex to autophagic membranes by specifically recognizing the membrane protein Atg9. This interaction is inhibited by the two regulatory subunits Atg31 and Atg29. Engagement of the Atg1–Atg13 subcomplex restores the Atg9-binding and membrane-tethering activity of Atg17. Our data help to unravel the mechanism that controls Atg17-mediated tethering of Atg9-vesicles, providing the molecular basis to understand initiation of autophagosome-biogenesis. Autophagosome biogenesis is initiated by recruitment of Atg9-vesicles to the phagophore assembly site. Here Rao et al. use a reconstituted in vitro system to describe the mechanism by which activation of the Atg1-kinase complex from its constituent parts recruits and tethers Atg9-vesicles.