2. Academic Validation
  3. ATM functions at the peroxisome to induce pexophagy in response to ROS

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.
Jiangwei Zhang # 1,  Durga Nand Tripathi # 1,  Ji Jing # 1,  Angela Alexander 2,  Jinhee Kim 3,  Reid T Powell 1,  Ruhee Dere 1,  Jacqueline Tait-Mulder 4,  Ji-Hoon Lee 5,  Tanya T Paull 5,  Raj K Pandita 6,  Vijaya K Charaka 6,  Tej K Pandita 6,  Michael B Kastan 4 7,  Cheryl Lyn Walker 1
Affiliations

Affiliations

  • 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.
PMID: 26344566 DOI: 10.1038/ncb3230
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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