title: VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive clearance of ruptured lysosomes by autophagy.
abstract: Rupture of endosomes and lysosomes is a major cellular stress condition leading to cell death and degeneration. Here, we identified an essential role for the ubiquitin-directed AAA-ATPase, p97, in the clearance of damaged lysosomes by autophagy. Upon damage, p97 translocates to lysosomes and there cooperates with a distinct set of cofactors including UBXD1, PLAA, and the deubiquitinating enzyme YOD1, which we term ELDR components for Endo-Lysosomal Damage Response. Together, they act downstream of K63-linked ubiquitination and p62 recruitment, and selectively remove K48-linked ubiquitin conjugates from a subpopulation of damaged lysosomes to promote autophagosome formation. Lysosomal clearance is also compromised in MEFs harboring a p97 mutation that causes inclusion body myopathy and neurodegeneration, and damaged lysosomes accumulate in affected patient tissue carrying the mutation. Moreover, we show that p97 helps clear late endosomes/lysosomes ruptured by endocytosed tau fibrils. Thus, our data reveal an important mechanism of how p97 maintains lysosomal homeostasis, and implicate the pathway as a modulator of degenerative diseases.
authors.affiliation: Molecular Biology I, Faculty of Biology, Centre for Medical Biotechnology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Chrisovalantis
authors.initials: C
authors.lastname: Papadopoulos
authors.affiliation: Molecular Biology I, Faculty of Biology, Centre for Medical Biotechnology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Kirchner
authors.affiliation: Molecular Biology I, Faculty of Biology, Centre for Medical Biotechnology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Bug
authors.affiliation: Molecular Biology I, Faculty of Biology, Centre for Medical Biotechnology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Grum
authors.affiliation: Molecular Biology I, Faculty of Biology, Centre for Medical Biotechnology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Koerver
authors.affiliation: Imaging Center Campus Essen, Faculty of Biology, Centre for Medical Biotechnology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Schulze
authors.affiliation: Molecular Biology I, Faculty of Biology, Centre for Medical Biotechnology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Poehler
authors.affiliation: Molecular Biology I, Faculty of Biology, Centre for Medical Biotechnology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Alina
authors.initials: A
authors.lastname: Dressler
authors.affiliation: Molecular Biology I, Faculty of Biology, Centre for Medical Biotechnology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Fengler
authors.affiliation: Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA.
authors.forename: Khalid
authors.initials: K
authors.lastname: Arhzaouy
authors.affiliation: Microbiology, Faculty of Biology, Centre for Medical Biotechnology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Vanda
authors.initials: V
authors.lastname: Lux
authors.affiliation: Microbiology, Faculty of Biology, Centre for Medical Biotechnology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Ehrmann
authors.affiliation: Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA.
authors.forename: Conrad C
authors.initials: CC
authors.lastname: Weihl
authors.affiliation: Molecular Biology I, Faculty of Biology, Centre for Medical Biotechnology, University of Duisburg-Essen, Essen, Germany hemmo.meyer@uni-due.de.
authors.forename: Hemmo
authors.identifier: 0000-0003-1883-1796
authors.initials: H
authors.lastname: Meyer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D011506:Proteins / Q000378:metabolism*; D013869:Thiolester Hydrolases / Q000378:metabolism*; D000074405:Valosin Containing Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D011506:Proteins; C533572:UBXN6 protein, human; C055324:phospholipase A2-activating protein; C545663:YOD1 protein, human; D013869:Thiolester Hydrolases; D010450:Endopeptidases; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse
keywords: AAA+‐type ATPase; autophagy; lysosomal membrane permeabilization; multisystem proteinopathy‐1; ubiquitin