title: Hsc70-4 Deforms Membranes to Promote Synaptic Protein Turnover by Endosomal Microautophagy.
abstract: Synapses are often far from their cell bodies and must largely independently cope with dysfunctional proteins resulting from synaptic activity and stress. To identify membrane-associated machines that can engulf synaptic targets destined for degradation, we performed a large-scale in vitro liposome-based screen followed by functional studies. We identified a presynaptically enriched chaperone Hsc70-4 that bends membranes based on its ability to oligomerize. This activity promotes endosomal microautophagy and the turnover of specific synaptic proteins. Loss of microautophagy slows down neurotransmission while gain of microautophagy increases neurotransmission. Interestingly, Sgt, a cochaperone of Hsc70-4, is able to switch the activity of Hsc70-4 from synaptic endosomal microautophagy toward chaperone activity. Hence, Hsc70-4 controls rejuvenation of the synaptic protein pool in a dual way: either by refolding proteins together with Sgt, or by targeting them for degradation by facilitating endosomal microautophagy based on its membrane deforming activity.
authors.affiliation: KU Leuven, Center for Human Genetics, Leuven Institute for Neurodegenerative Disease (LIND), Laboratory of Neuronal Communication, Herestraat 49, 3000 Leuven, Belgium; VIB Center for the Biology of Disease, Leuven Institute for Neurodegenerative Disease (LIND), Laboratory of Neuronal Communication, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Valerie
authors.initials: V
authors.lastname: Uytterhoeven
authors.affiliation: KU Leuven, Center for Human Genetics, Leuven Institute for Neurodegenerative Disease (LIND), Laboratory of Neuronal Communication, Herestraat 49, 3000 Leuven, Belgium; VIB Center for the Biology of Disease, Leuven Institute for Neurodegenerative Disease (LIND), Laboratory of Neuronal Communication, Herestraat 49, 3000 Leuven, Belgium. Electronic address: elsa.lauwers@cme.vib-kuleuven.be.
authors.forename: Elsa
authors.initials: E
authors.lastname: Lauwers
authors.affiliation: KU Leuven, Center for Human Genetics, Leuven Institute for Neurodegenerative Disease (LIND), Laboratory of Neuronal Communication, Herestraat 49, 3000 Leuven, Belgium; VIB Center for the Biology of Disease, Leuven Institute for Neurodegenerative Disease (LIND), Laboratory of Neuronal Communication, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Ine
authors.initials: I
authors.lastname: Maes
authors.affiliation: KU Leuven, Center for Human Genetics, Leuven Institute for Neurodegenerative Disease (LIND), Laboratory of Neuronal Communication, Herestraat 49, 3000 Leuven, Belgium; VIB Center for the Biology of Disease, Leuven Institute for Neurodegenerative Disease (LIND), Laboratory of Neuronal Communication, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Miskiewicz
authors.affiliation: Groningen Biomolecular Sciences and Biotechnology Institute and Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands.
authors.forename: Manuel N
authors.initials: MN
authors.lastname: Melo
authors.affiliation: KU Leuven, Center for Human Genetics, Leuven Institute for Neurodegenerative Disease (LIND), Laboratory of Neuronal Communication, Herestraat 49, 3000 Leuven, Belgium; VIB Center for the Biology of Disease, Leuven Institute for Neurodegenerative Disease (LIND), Laboratory of Neuronal Communication, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Jef
authors.initials: J
authors.lastname: Swerts
authors.affiliation: KU Leuven, Center for Human Genetics, Leuven Institute for Neurodegenerative Disease (LIND), Laboratory of Neuronal Communication, Herestraat 49, 3000 Leuven, Belgium; VIB Center for the Biology of Disease, Leuven Institute for Neurodegenerative Disease (LIND), Laboratory of Neuronal Communication, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Sabine
authors.initials: S
authors.lastname: Kuenen
authors.affiliation: KU Leuven, Center for Human Genetics, Leuven Institute for Neurodegenerative Disease (LIND), Laboratory of Neuronal Communication, Herestraat 49, 3000 Leuven, Belgium; VIB Center for the Biology of Disease, Leuven Institute for Neurodegenerative Disease (LIND), Laboratory of Neuronal Communication, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Rafaël
authors.initials: R
authors.lastname: Wittocx
authors.affiliation: VIB Bio-Imaging Core Facility, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Nikky
authors.initials: N
authors.lastname: Corthout
authors.affiliation: Groningen Biomolecular Sciences and Biotechnology Institute and Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands.
authors.forename: Siewert-Jan
authors.initials: SJ
authors.lastname: Marrink
authors.affiliation: VIB Bio-Imaging Core Facility, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Munck
authors.affiliation: KU Leuven, Center for Human Genetics, Leuven Institute for Neurodegenerative Disease (LIND), Laboratory of Neuronal Communication, Herestraat 49, 3000 Leuven, Belgium; VIB Center for the Biology of Disease, Leuven Institute for Neurodegenerative Disease (LIND), Laboratory of Neuronal Communication, Herestraat 49, 3000 Leuven, Belgium. Electronic address: patrik.verstreken@cme.vib-kuleuven.be.
authors.forename: Patrik
authors.initials: P
authors.lastname: Verstreken
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics; D055032:Electron Microscope Tomography; D011992:Endosomes / Q000378:metabolism / Q000648:ultrastructure; D004926:Escherichia coli; D029968:Escherichia coli Proteins; D050883:HSC70 Heat-Shock Proteins / Q000235:genetics*; D008856:Microscopy, Fluorescence; D018832:Molecular Chaperones; D058105:Polymerization; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D013570:Synaptic Membranes / Q000378:metabolism* / Q000648:ultrastructure; D009435:Synaptic Transmission; D013572:Synaptic Vesicles / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D029721:Drosophila Proteins; D029968:Escherichia coli Proteins; D050883:HSC70 Heat-Shock Proteins; C424447:Hsc70-4 protein, Drosophila; D018832:Molecular Chaperones; D029701:Saccharomyces cerevisiae Proteins