title: Lysosomal mTORC2/PHLPP1/Akt Regulate Chaperone-Mediated Autophagy.
abstract: Chaperone-mediated autophagy (CMA), a selective form of degradation of cytosolic proteins in lysosomes, contributes to maintenance of proteostasis and to the cellular adaptation to stress. CMA substrates are delivered by a cytosolic chaperone to the lysosomal surface, where, upon unfolding, they are internalized through a membrane translocation complex. The molecular components that participate in CMA substrate targeting and translocation are well characterized, but those involved in CMA regulation remain mostly unknown. In this study, we have identified that CMA is under the positive control of the phosphatase PHLPP1 that associates with the lysosomal membrane and counteracts the inhibitory effect of mTORC2 on CMA. Lysosomal Akt, a target of the mTORC2/PHLPP1 kinase-phosphatase pair, modulates CMA activity by controlling the dynamics of assembly and disassembly of the CMA translocation complex at the lysosomal membrane. The lysosomal mTORC2/PHLPP1/Akt axis could become a target to restore CMA dysfunction in aging and disease.
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Esperanza
authors.initials: E
authors.lastname: Arias
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Koga
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Diaz
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Enric
authors.initials: E
authors.lastname: Mocholi
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Bindi
authors.initials: B
authors.lastname: Patel
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: ana-maria.cuervo@einstein.yu.edu.
authors.forename: Ana María
authors.initials: AM
authors.lastname: Cuervo
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006801:Humans; D008099:Liver / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D018832:Molecular Chaperones; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C400601:PHLPP1 protein, human; C519282:PHLPP1 protein, mouse; C553451:PHLPP1 protein, rat; D010749:Phosphoprotein Phosphatases