ATM functions at the peroxisome to induce pexophagy in response to ROS

Nat Cell Biol. 2015 Oct;17(10):1259-1269. doi: 10.1038/ncb3230. Epub 2015 Sep 7.

Abstract

Peroxisomes are highly metabolic, autonomously replicating organelles that generate reactive oxygen species (ROS) as a by-product of fatty acid β-oxidation. Consequently, cells must maintain peroxisome homeostasis, or risk pathologies associated with too few peroxisomes, such as peroxisome biogenesis disorders, or too many peroxisomes, inducing oxidative damage and promoting diseases such as cancer. We report that the PEX5 peroxisome import receptor binds ataxia-telangiectasia mutated (ATM) and localizes this kinase to the peroxisome. In response to ROS, ATM signalling activates ULK1 and inhibits mTORC1 to induce autophagy. Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser 141, which promotes PEX5 monoubiquitylation at Lys 209, and recognition of ubiquitylated PEX5 by the autophagy adaptor protein p62, directing the autophagosome to peroxisomes to induce pexophagy. These data reveal an important new role for ATM in metabolism as a sensor of ROS that regulates pexophagy.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Ataxia Telangiectasia Mutated Proteins / metabolism*
  • Autophagy*
  • Blotting, Western
  • Cells, Cultured
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Hydrogen Peroxide / pharmacology
  • MCF-7 Cells
  • Mechanistic Target of Rapamycin Complex 1
  • Mice, Knockout
  • Microscopy, Electron
  • Microscopy, Fluorescence
  • Multiprotein Complexes / metabolism
  • Mutation
  • Peroxisome-Targeting Signal 1 Receptor
  • Peroxisomes / metabolism*
  • Peroxisomes / ultrastructure
  • Phagosomes / metabolism
  • Phagosomes / ultrastructure
  • Phosphorylation / drug effects
  • Protein Binding
  • RNA Interference
  • Reactive Oxygen Species / metabolism*
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequestosome-1 Protein
  • Serine / genetics
  • Serine / metabolism
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Multiprotein Complexes
  • PEX5 protein, human
  • Peroxisome-Targeting Signal 1 Receptor
  • Pex5 protein, mouse
  • Reactive Oxygen Species
  • Receptors, Cytoplasmic and Nuclear
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Serine
  • Hydrogen Peroxide
  • TOR Serine-Threonine Kinases
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Mechanistic Target of Rapamycin Complex 1