Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria
Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria
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DOI：
10.1073/pnas.1523926113
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发表时间：
2016-04-12
影响因子：
11.1
通讯作者：
Dikic, Ivan
中科院分区：
文献类型：
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作者：
Richter, Benjamin;Sliter, Danielle A.;Dikic, Ivan
受损线粒体的选择性自噬需要自噬受体视神经磷酸酶（OPTN），NDP 52（CALCOCO 2），TAX 1BP 1和p62（SQSTM 1）将泛素化货物连接到自噬膜。通过使用定量蛋白质组学，我们发现Tank结合激酶1（TBK 1）磷酸化了几个自噬相关位点上的所有四种受体，包括OPTN和p62/SQSTM 1的泛素和LC 3结合结构域以及NDP 52和TAX 1BP 1的SKICH结构域。TBK 1与OPTN的组成性相互作用和OPTN结合泛素链的能力对于TBK 1募集和线粒体上的激酶活化是必不可少的。TBK 1又磷酸化OPTN的UBAN结构域S473，从而扩大OPTN与不同Ub链的结合能力。结合S177和S513的磷酸化，这种翻译后修饰促进OPTN/TBK 1在泛素化的受损线粒体上的募集和保留。此外，在S473上的OPTN的磷酸化使得能够与pS 65 Ub链结合，并且还涉及PINK 1驱动的和不依赖于Parkin的线粒体自噬。因此，TBK 1介导的自噬受体磷酸化产生了一个信号放大环，在受损线粒体的选择性自噬中起作用。
Selective autophagy of damaged mitochondria requires autophagy receptors optineurin (OPTN), NDP52 (CALCOCO2), TAX1BP1, and p62 (SQSTM1) linking ubiquitinated cargo to autophagic membranes. By using quantitative proteomics, we show that Tank-binding kinase 1 (TBK1) phosphorylates all four receptors on several autophagy-relevant sites, including the ubiquitin-and LC3-binding domains of OPTN and p62/SQSTM1 as well as the SKICH domains of NDP52 and TAX1BP1. Constitutive interaction of TBK1 with OPTN and the ability of OPTN to bind to ubiquitin chains are essential for TBK1 recruitment and kinase activation on mitochondria. TBK1 in turn phosphorylates OPTN's UBAN domain at S473, thereby expanding the binding capacity of OPTN to diverse Ub chains. In combination with phosphorylation of S177 and S513, this posttranslational modification promotes recruitment and retention of OPTN/TBK1 on ubiquitinated, damaged mitochondria. Moreover, phosphorylation of OPTN on S473 enables binding to pS65 Ub chains and is also implicated in PINK1-driven and Parkin-independent mitophagy. Thus, TBK1-mediated phosphorylation of autophagy receptors creates a signal amplification loop operating in selective autophagy of damaged mitochondria.