title: A new role for ATM in selective autophagy of peroxisomes (pexophagy).
abstract: Peroxisomes are autonomously replicating and highly metabolic organelles necessary for β-oxidation of fatty acids, a process that generates large amounts of reactive oxygen species (ROS). Maintaining a balance between biogenesis and degradation of peroxisomes is essential to maintain cellular redox balance, but how cells do this has remained somewhat of a mystery. While it is known that peroxisomes can be degraded via selective autophagy (pexophagy), little is known about how mammalian cells regulate pexophagy to maintain peroxisome homeostasis. We have uncovered a mechanism for regulating pexophagy in mammalian cells that defines a new role for ATM (ATM serine/threonine kinase) kinase as a "first responder" to peroxisomal ROS. ATM is delivered to the peroxisome by the PEX5 import receptor, which recognizes an SRL sequence located at the C terminus of ATM to localize this kinase to peroxisomes. In response to ROS, the ATM kinase is activated and performs 2 functions: i) it signals to AMPK, which activates TSC2 to suppresses MTORC1 and phosphorylates ULK1 to induce autophagy, and ii) targets specific peroxisomes for pexophagy by phosphorylating PEX5 at Ser141, which triggers ubiquitination of PEX5 at Lys209 and binding of the autophagy receptor protein SQSTM1/p62 to induce pexophagy.
authors.affiliation: a Center for Translation Cancer Research, Institute of Bioscience & Technology, Texas A&M University Health Science Center , Houston , TX , USA.
authors.forename: Durga Nand
authors.initials: DN
authors.lastname: Tripathi
authors.affiliation: a Center for Translation Cancer Research, Institute of Bioscience & Technology, Texas A&M University Health Science Center , Houston , TX , USA.
authors.forename: Jiangwei
authors.initials: J
authors.lastname: Zhang
authors.affiliation: a Center for Translation Cancer Research, Institute of Bioscience & Technology, Texas A&M University Health Science Center , Houston , TX , USA.
authors.forename: Ji
authors.initials: J
authors.lastname: Jing
authors.affiliation: a Center for Translation Cancer Research, Institute of Bioscience & Technology, Texas A&M University Health Science Center , Houston , TX , USA.
authors.forename: Ruhee
authors.initials: R
authors.lastname: Dere
authors.affiliation: a Center for Translation Cancer Research, Institute of Bioscience & Technology, Texas A&M University Health Science Center , Houston , TX , USA.
authors.forename: Cheryl Lyn
authors.initials: CL
authors.lastname: Walker
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D001343:Autophagy; D006801:Humans; D008322:Mammals / Q000378:metabolism; D008954:Models, Biological; D020675:Peroxisomes / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D064007:Ataxia Telangiectasia Mutated Proteins