Format

Send to

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

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

Author information

1
Center for Translational Cancer Research, Institute for Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030, USA.
2
Department of Experimental Radiation Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
3
Korea Institute of Oriental Medicine, Dajeon, 305-811, South Korea.
4
Departments of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105.
5
The Howard Hughes Medical Institute, Department of Molecular Genetics and Microbiology, University of Texas, Austin, TX 78712.
6
Department of Radiation Oncology, Houston Methodist Hospital, Houston, TX 77030, USA.
7
Pharmacology and Cancer Biology, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.
#
Contributed equally

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.

Comment in

PMID:
26344566
PMCID:
PMC4589490
DOI:
10.1038/ncb3230
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center