ATM functions at the peroxisome to induce pexophagy in response to ROS.
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.
Center for Translational Cancer Research, Institute for Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030, USA.
Jiangwei
J
Zhang
Center for Translational Cancer Research, Institute for Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030, USA.
Durga Nand
DN
Tripathi
Center for Translational Cancer Research, Institute for Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030, USA.
Ji
J
Jing
Department of Experimental Radiation Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Angela
A
Alexander
Korea Institute of Oriental Medicine, Dajeon, 305-811, South Korea.
Jinhee
J
Kim
Center for Translational Cancer Research, Institute for Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030, USA.
Reid T
RT
Powell
Center for Translational Cancer Research, Institute for Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030, USA.
Ruhee
R
Dere
Departments of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Jacqueline
J
Tait-Mulder
The Howard Hughes Medical Institute, Department of Molecular Genetics and Microbiology, University of Texas, Austin, TX 78712.
Ji-Hoon
JH
Lee
The Howard Hughes Medical Institute, Department of Molecular Genetics and Microbiology, University of Texas, Austin, TX 78712.
Tanya T
TT
Paull
Department of Radiation Oncology, Houston Methodist Hospital, Houston, TX 77030, USA.
Raj K
RK
Pandita
Department of Radiation Oncology, Houston Methodist Hospital, Houston, TX 77030, USA.
Vijaya K
VK
Charaka
Department of Radiation Oncology, Houston Methodist Hospital, Houston, TX 77030, USA.
Tej K
TK
Pandita
Departments of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105.|Pharmacology and Cancer Biology, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.
Michael B
MB
Kastan
Center for Translational Cancer Research, Institute for Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030, USA.
Cheryl Lyn
CL
Walker
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy; D015153:Blotting, Western; D002478:Cells, Cultured; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D061986:MCF-7 Cells; D000076222:Mechanistic Target of Rapamycin Complex 1; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D046912:Multiprotein Complexes / Q000378:metabolism; D009154:Mutation; D000074435:Peroxisome-Targeting Signal 1 Receptor; D020675:Peroxisomes / Q000378:metabolism* / Q000648:ultrastructure; D010588:Phagosomes / Q000378:metabolism / Q000648:ultrastructure; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071456:Sequestosome-1 Protein; D012694:Serine / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D046912:Multiprotein Complexes; C000614264:PEX5 protein, human; D000074435:Peroxisome-Targeting Signal 1 Receptor; C000614265:Pex5 protein, mouse; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D012694:Serine; D006861:Hydrogen Peroxide; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases