Molecular determinants of the crosstalk between endosomal microautophagy and chaperone-mediated autophagy
Gregory J. Krause,
Philipp Kirchner,
Barbara Stiller,
Kateryna Morozova,
Antonio Diaz,
Kuei-Ho Chen,
Nevan J. Krogan,
Esperanza Agullo-Pascual,
Cristina C. Clement,
Kristen Lindenau,
Danielle L. Swaney,
Shilpa Dilipkumar,
Jose Javier Bravo-Cordero,
Laura Santambrogio,
Ana Maria Cuervo
Affiliations
Gregory J. Krause
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
Philipp Kirchner
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
Barbara Stiller
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
Kateryna Morozova
Department of Radiation Oncology, Weill Cornell School of Medicine, New York, NY 10021, USA
Antonio Diaz
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
Kuei-Ho Chen
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; The J. David Gladstone Institutes, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA
Nevan J. Krogan
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; The J. David Gladstone Institutes, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA
Esperanza Agullo-Pascual
Microscopy CoRE, Dean’s CoREs, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Cristina C. Clement
Department of Radiation Oncology, Weill Cornell School of Medicine, New York, NY 10021, USA
Kristen Lindenau
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
Danielle L. Swaney
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; The J. David Gladstone Institutes, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA
Shilpa Dilipkumar
Microscopy CoRE, Dean’s CoREs, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Jose Javier Bravo-Cordero
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Laura Santambrogio
Department of Radiation Oncology, Weill Cornell School of Medicine, New York, NY 10021, USA; Corresponding author
Ana Maria Cuervo
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; Corresponding author
Summary: Chaperone-mediated autophagy (CMA) and endosomal microautophagy (eMI) are pathways for selective degradation of cytosolic proteins in lysosomes and late endosomes, respectively. These autophagic processes share as a first step the recognition of the same five-amino-acid motif in substrate proteins by the Hsc70 chaperone, raising the possibility of coordinated activity of both pathways. In this work, we show the existence of a compensatory relationship between CMA and eMI and identify a role for the chaperone protein Bag6 in triage and internalization of eMI substrates into late endosomes. Association and dynamics of Bag6 at the late endosome membrane change during starvation, a stressor that, contrary to other autophagic pathways, causes a decline in eMI activity. Collectively, these results show a coordinated function of eMI with CMA, identify the interchangeable subproteome degraded by these pathways, and start to elucidate the molecular mechanisms that facilitate the switch between them.
