Reduced endosomal microautophagy activity in aging associates with enhanced exocyst-mediated protein secretion.

Autor: Krause GJ; Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA.; Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York, USA., Diaz A; Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA.; Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York, USA., Jafari M; Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA.; Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York, USA., Khawaja RR; Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA.; Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York, USA., Agullo-Pascual E; Microscopy and Advanced Bioimaging Core, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Santiago-Fernández O; Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA.; Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York, USA., Richards AL; Department of Cellular Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA.; The J. David Gladstone Institutes, San Francisco, California, USA.; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, California, USA., Chen KH; Department of Cellular Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA.; The J. David Gladstone Institutes, San Francisco, California, USA.; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, California, USA., Dmitriev P; Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA.; Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York, USA., Sun Y; Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA., See SK; Department of Biochemistry and Biophysics, Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, California, USA., Abdelmohsen K; Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, Maryland, USA., Mazan-Mamczarz K; Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, Maryland, USA., Krogan NJ; Department of Cellular Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA.; The J. David Gladstone Institutes, San Francisco, California, USA.; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, California, USA., Gorospe M; Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, Maryland, USA., Swaney DL; Department of Cellular Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA.; The J. David Gladstone Institutes, San Francisco, California, USA.; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, California, USA., Sidoli S; Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA., Bravo-Cordero JJ; Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Kampmann M; Department of Biochemistry and Biophysics, Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, California, USA., Cuervo AM; Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA.; Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York, USA.
Jazyk: angličtina
Zdroj: Aging cell [Aging Cell] 2022 Oct; Vol. 21 (10), pp. e13713. Date of Electronic Publication: 2022 Sep 18.
DOI: 10.1111/acel.13713
Abstrakt: Autophagy is essential for protein quality control and regulation of the functional proteome. Failure of autophagy pathways with age contributes to loss of proteostasis in aged organisms and accelerates the progression of age-related diseases. In this work, we show that activity of endosomal microautophagy (eMI), a selective type of autophagy occurring in late endosomes, declines with age and identify the sub-proteome affected by this loss of function. Proteomics of late endosomes from old mice revealed an aberrant glycation signature for Hsc70, the chaperone responsible for substrate targeting to eMI. Age-related Hsc70 glycation reduces its stability in late endosomes by favoring its organization into high molecular weight protein complexes and promoting its internalization/degradation inside late endosomes. Reduction of eMI with age associates with an increase in protein secretion, as late endosomes can release protein-loaded exosomes upon plasma membrane fusion. Our search for molecular mediators of the eMI/secretion switch identified the exocyst-RalA complex, known for its role in exocytosis, as a novel physiological eMI inhibitor that interacts with Hsc70 and acts directly at the late endosome membrane. This inhibitory function along with the higher exocyst-RalA complex levels detected in late endosomes from old mice could explain, at least in part, reduced eMI activity with age. Interaction of Hsc70 with components of the exocyst-RalA complex places this chaperone in the switch from eMI to secretion. Reduced intracellular degradation in favor of extracellular release of undegraded material with age may be relevant to the spreading of proteotoxicity associated with aging and progression of proteinopathies.
(© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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