Figure 1. p97 with its cofactors drive clearance of damaged lysosomes by autophagy.

Upon membrane rupture, for example, caused by endocytosed tau fibrils, galectin‐3 marks membrane remnants and K63‐Ub of membrane proteins mediate p62 recruitment to initiate the autophagic response. A subset of lysosomes is also marked by K48‐Ub that needs to be removed by ELDR components to promote autophagosome formation and lysosome clearance. Compromised ELDR function, for example, due to p97 mutations that cause inclusion body myopathy and neurodegeneration, results in impaired turnover of K48‐Ub and failure of lysosome clearance.