VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive clearance of ruptured lysosomes by autophagy

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. Synopsis The AAA‐ATPase VCP/p97 governs an endolysosomal damage response pathway (ELDR) that ensures survival after lysosomal rupture and promotes autophagic clearance of the damaged organelles. p97 is essential for autophagy of damaged lysosomes (lysophagy) and this is affected by p97 disease mutations. p97 is recruited acutely to damaged lysosomes and cooperates with its cofactors UBXD1, PLAA, and the deubiquitinating enzyme YOD1, jointly termed the ELDR components. The ELDR components remove K48‐linked ubiquitin conjugates from damaged lysosomes. K48 removal promotes autophagosome formation and clearance of damaged lysosomes. Graphical Abstract The AAA‐ATPase VCP/p97 governs an endolysosomal damage response pathway (ELDR) that ensures survival after lysosomal rupture and promotes autophagic clearance of the damaged organelles.