TY - JOUR
T1 - ATM functions at the peroxisome to induce pexophagy in response to ROS
AU - Zhang, Jiangwei
AU - Tripathi, Durga Nand
AU - Jing, Ji
AU - Alexander, Angela
AU - Kim, Jinhee
AU - Powell, Reid T.
AU - Dere, Ruhee
AU - Tait-Mulder, Jacqueline
AU - Lee, Ji Hoon
AU - Paull, Tanya T.
AU - Pandita, Raj K.
AU - Charaka, Vijaya K.
AU - Pandita, Tej K.
AU - Kastan, Michael B.
AU - Walker, Cheryl Lyn
PY - 2015/10/3
Y1 - 2015/10/3
N2 - 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.
AB - 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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U2 - 10.1038/ncb3230
DO - 10.1038/ncb3230
M3 - Article
C2 - 26344566
AN - SCOPUS:84942982653
VL - 17
SP - 1259
EP - 1269
JO - Nature
JF - Nature
SN - 0028-0836
IS - 10
ER -