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

Nature Cell Biology
Jiangwei ZhangCheryl Lyn Walker

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.

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Datasets Mentioned

BETA
GM05849

Methods Mentioned

BETA
electron microscopy
ubiquitination
immunoprecipitation
Transfection
transfections
PCR
density gradient centrifugation
Protein Assay
chromosomal aberrations

Software Mentioned

Imaris
GraphPad Prism
SoftWoRx
ImageQuantTL
ImageJ

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