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

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.

Heo JM ，Ordureau A ，Paulo JA ，Rinehart J ，Harper JW ... -  《-》

Dynamic recruitment and activation of ALS-associated TBK1 with its target optineurin are required for efficient mitophagy.

Moore AS ，Holzbaur EL 《-》

Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria.

Richter B ，Sliter DA ，Herhaus L ，Stolz A ，Wang C ，Beli P ，Zaffagnini G ，Wild P ，Martens S ，Wagner SA ，Youle RJ ，Dikic I ... -  《-》

Defining roles of PARKIN and ubiquitin phosphorylation by PINK1 in mitochondrial quality control using a ubiquitin replacement strategy.

Ordureau A ，Heo JM ，Duda DM ，Paulo JA ，Olszewski JL ，Yanishevski D ，Rinehart J ，Schulman BA ，Harper JW ... -  《-》

RAB7A phosphorylation by TBK1 promotes mitophagy via the PINK-PARKIN pathway.

Heo JM ，Ordureau A ，Swarup S ，Paulo JA ，Shen K ，Sabatini DM ，Harper JW ... -  《Science Advances》