The PINK1-PARKIN Mitochondrial Ubiquitylation Pathway Drives a Program of OPTN/NDP52 Recruitment and TBK1 Activation to Promote Mitophagy

被引：711

作者：

Heo, Jin-Mi ^{[1
]}

Ordureau, Alban ^{[1
]}

Paulo, Joao A. ^{[1
]}

Rinehart, Jesse ^{[2
]}

Harper, J. Wade ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA

[2] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, Syst Biol Inst, New Haven, CT 06520 USA

来源：

MOLECULAR CELL | 2015年 / 60卷 / 01期

关键词：

BINDING KINASE 1; AUTOPHAGY RECEPTOR; UBIQUITIN CHAINS; PARKIN; OPTINEURIN; PINK1; PHOSPHORYLATION; ROLES; NDP52; NEMO;

D O I：

10.1016/j.molcel.2015.08.016

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 autophagy adaptor recruitment concomitantly with activation of the TBK1 kinase, which physically associates with OPTN, NDP52, and SQSTM1. 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, and mechanistically links genes mutated in Parkinson's disease and amyotrophic lateral sclerosis in a common selective autophagy pathway.

引用

页码：7 / 20

页数：14

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