The Ubiquitin Kinase PINK1 Recruits Autophagy Receptors to Induce Mitophagy

Nature. 2015 Aug 20;524(7565):309-314. doi: 10.1038/nature14893. Epub 2015 Aug 12.

Abstract

Protein aggregates and damaged organelles are tagged with ubiquitin chains to trigger selective autophagy. To initiate mitophagy, the ubiquitin kinase PINK1 phosphorylates ubiquitin to activate the ubiquitin ligase parkin, which builds ubiquitin chains on mitochondrial outer membrane proteins, where they act to recruit autophagy receptors. Using genome editing to knockout five autophagy receptors in HeLa cells, here we show that two receptors previously linked to xenophagy, NDP52 and optineurin, are the primary receptors for PINK1- and parkin-mediated mitophagy. PINK1 recruits NDP52 and optineurin, but not p62, to mitochondria to activate mitophagy directly, independently of parkin. Once recruited to mitochondria, NDP52 and optineurin recruit the autophagy factors ULK1, DFCP1 and WIPI1 to focal spots proximal to mitochondria, revealing a function for these autophagy receptors upstream of LC3. This supports a new model in which PINK1-generated phospho-ubiquitin serves as the autophagy signal on mitochondria, and parkin then acts to amplify this signal. This work also suggests direct and broader roles for ubiquitin phosphorylation in other autophagy pathways.

Publication types

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

MeSH terms

  • Autophagy / physiology*
  • Autophagy-Related Protein-1 Homolog
  • Autophagy-Related Proteins
  • Carrier Proteins / metabolism
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Membrane Proteins / metabolism
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / metabolism
  • Mitochondrial Proteins / metabolism
  • Mitophagy / physiology*
  • Models, Biological
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction
  • Transcription Factor TFIIIA / metabolism*
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Autophagy-Related Proteins
  • CALCOCO2 protein, human
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • MAP1LC3B protein, human
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Mitochondrial Proteins
  • Nuclear Proteins
  • OPTN protein, human
  • Transcription Factor TFIIIA
  • Ubiquitin
  • WIPI-1 protein, human
  • ZFYVE1 protein, human
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Protein Kinases
  • Autophagy-Related Protein-1 Homolog
  • PTEN-induced putative kinase
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human
  • ULK1 protein, human