Spatiotemporal Control of ULK1 Activation by NDP52 and TBK1 during Selective Autophagy
Spatiotemporal Control of ULK1 Activation by NDP52 and TBK1 during Selective Autophagy
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选择性自噬过程中NDP52和TBK1对ULK1激活的时空调控
DOI：
10.1016/j.molcel.2019.02.010
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发表时间：
2019-04-18
期刊：
影响因子：
16
通讯作者：
Youle, Richard J.
中科院分区：
文献类型：
--
作者：
Vargas, Jose Norberto S.;Wang, Chunxin;Youle, Richard J.
选择性自噬回收受损的细胞器并清除细胞内病原体，以防止其异常积累。 ULK1 激酶如何在选择性自噬事件期间被靶向和激活仍有待阐明。在本研究中，我们使用化学诱导二聚化 (CID) 检测与 CRISPR KO 系联用，系统分析选择性自噬体生物发生的分子基础。我们证明，NDP52 在线粒体或过氧化物酶体上的异位放置足以通过局部定位和激活 ULK1 复合物来启动选择性自噬。 NDP52 诱导线粒体自噬的能力取决于其与 FIP200/ULK1 复合物的相互作用，而 TBK1 可以促进这种相互作用。将 ULK1 异位连接到货物上绕过了对自噬受体和 TBK1 的要求。 ULK1 的局部激活独立于 AMPK 和 mTOR。我们的研究结果提供了选择性自噬的简约模型，该模型强调了自噬受体和 TBK1 之间 ULK1 复合物定位的协调是靶向自噬体生物发生的主要驱动因素。
Selective autophagy recycles damaged organelles and clears intracellular pathogens to prevent their aberrant accumulation. How ULK1 kinase is targeted and activated during selective autophagic events remains to be elucidated. In this study, we used chemically inducible dimerization (CID) assays in tandem with CRISPR KO lines to systematically analyze the molecular basis of selective autophagosome biogenesis. We demonstrate that ectopic placement of NDP52 on mitochondria or peroxisomes is sufficient to initiate selective autophagy by focally localizing and activating the ULK1 complex. The capability of NDP52 to induce mitophagy is dependent on its interaction with the FIP200/ULK1 complex, which is facilitated by TBK1. Ectopically tethering ULK1 to cargo bypasses the requirement for autophagy receptors and TBK1. Focal activation of ULK1 occurs independently of AMPK and mTOR. Our findings provide a parsimonious model of selective autophagy, which highlights the coordination of ULK1 complex localization by autophagy receptors and TBK1 as principal drivers of targeted autophagosome biogenesis.