The PINK1-PARKIN Mitochondrial Ubiquitylation Pathway Drives a Program of OPTN/NDP52 Recruitment and TBK1 Activation to Promote Mitophagy.
The PINK1-PARKIN Mitochondrial Ubiquitylation Pathway Drives a Program of OPTN/NDP52 Recruitment and TBK1 Activation to Promote Mitophagy.
复制标题
DOI：
10.1016/j.molcel.2015.08.016
复制
发表时间：
2015-10-01
期刊：
影响因子：
16
通讯作者：
Harper JW
中科院分区：
文献类型：
--
作者：
Heo JM;Ordureau A;Paulo JA;Rinehart J;Harper JW
线粒体受损不利于细胞内环境的稳定。去除受损线粒体的一种机制涉及PINK1-Parkin通路，该通路通过多泛素化受损线粒体来促进有丝分裂。我们报告说，线粒体上泛素链的组装触发了自噬适配器的招募，同时激活了与OPTN、NDP52和SQSTM1物理上相关的TBK1蛋白激酶。在HeLa细胞中完全激活TBK1需要OPTN和NDP52，以及OPTN泛素链结合。除了已知的OPTN中S177磷酸化在ATG8募集中的作用外，S473和S513上依赖于TBK1的磷酸化在体外促进泛素链结合，在体内促进TBK1激活、OPTN线粒体保留和有效的有丝分裂吞噬。这些数据揭示了一种自我强化的正反馈机制，该机制协调了TBK1依赖的自噬适配器磷酸化与线粒体上泛素链的组装，以促进有效的有丝分裂吞噬。类似的机制可能有助于适配器-蛋白质介导的其他类型的货物到自噬体内的递送。
Damaged mitochondria are detrimental to cellular homeostasis. One mechanism for removal of damaged mitochondria involves the PINK1-PARKIN pathway, which poly-ubiquitylates damaged mitochondria to promote mitophagy. We report that assembly of ubiquitin chains on mitochondria triggers the recruitment of autophagy adaptors concomitantly with activation of the TBK1 protein kinase, which physically associates with OPTN, NDP52, and SQSTM1. Full TBK1 activation in HeLa cells requires OPTN and NDP52, and OPTN ubiquitin chain binding. In addition to the known role of S177 phosphorylation in OPTN on ATG8 recruitment, TBK1-dependent phosphorylation on S473 and S513 promotes ubiquitin chain binding in vitro as well as TBK1 activation, OPTN mitochondrial retention, and efficient mitophagy in vivo. These data reveal a self-reinforcing positive feedback mechanism that coordinates TBK1-dependent autophagy adaptor phosphorylation with the assembly of ubiquitin chains on mitochondria to facilitate efficient mitophagy. Analogous mechanisms may facilitate adaptor-protein mediated delivery of other types of cargo to autophagosomes.