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

Mol Cell. 2015 Oct 1;60(1):7-20. doi: 10.1016/j.molcel.2015.08.016. Epub 2015 Sep 10.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Cell Cycle Proteins
  • HeLa Cells
  • Humans
  • Membrane Transport Proteins
  • Mitochondria / metabolism*
  • Mitophagy*
  • Nuclear Proteins / metabolism
  • Phosphorylation
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proteomics / methods
  • Sequestosome-1 Protein
  • Transcription Factor TFIIIA / metabolism
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination*

Substances

  • Adaptor Proteins, Signal Transducing
  • CALCOCO2 protein, human
  • Cell Cycle Proteins
  • Membrane Transport Proteins
  • Nuclear Proteins
  • OPTN protein, human
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Transcription Factor TFIIIA
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Protein Kinases
  • PTEN-induced putative kinase
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human