An ATG12‐ATG5‐TECPR1 E3‐like complex regulates unconventional LC3 lipidation at damaged lysosomes

Abstract

Lysosomal membrane damage represents a threat to cell viability. As such, cells have evolved sophisticated mechanisms to maintain lysosomal integrity. Small membrane lesions are detected and repaired by the endosomal sorting complex required for transport (ESCRT) machinery while more extensively damaged lysosomes are cleared by a galectin‐dependent selective macroautophagic pathway (lysophagy). In this study, we identify a novel role for the autophagosome‐lysosome tethering factor, TECPR1, in lysosomal membrane repair. Lysosomal damage promotes TECPR1 recruitment to damaged membranes via its N‐terminal dysferlin domain. This recruitment occurs upstream of galectin and precedes the induction of lysophagy. At the damaged membrane, TECPR1 forms an alternative E3‐like conjugation complex with the ATG12‐ATG5 conjugate to regulate ATG16L1‐independent unconventional LC3 lipidation. Abolishment of LC3 lipidation via ATG16L1/TECPR1 double knockout impairs lysosomal recovery following damage. image TECPR1 is recruited to damaged lysosomal membranes where it assembles into an alternative E3‐like complex with the ATG5‐ATG12 conjugate to regulate ATG16L1‐independent LC3 lipidation and promote lysosome repair. TECPR1 is recruited to damaged lysosomal membranes via its N‐terminal dysferlin domain TECPR1 can form an alternative E3‐like complex with ATG5‐ATG12 to regulate LC3 lipidation, independent of ATG16L1 Loss of TECPR1 and ATG16L1 impairs lysosomal recovery after damage