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VCP /p97 cooperates with YOD 1, UBXD 1 and PLAA to drive clearance of ruptured lysosomes by autophagy
Author(s) -
Papadopoulos Chrisovalantis,
Kirchner Philipp,
Bug Monika,
Grum Daniel,
Koerver Lisa,
Schulze Nina,
Poehler Robert,
Dressler Alina,
Fengler Sven,
Arhzaouy Khalid,
Lux Vanda,
Ehrmann Michael,
Weihl Conrad C,
Meyer Hemmo
Publication year - 2016
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201695148
Subject(s) - biology , autophagy , microbiology and biotechnology , biochemistry , apoptosis
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 ‐ ATP ase, 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 UBXD 1, PLAA , and the deubiquitinating enzyme YOD 1, 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 MEF s 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.