CASM regulates p62/KEAP1/NRF2 antioxidant responses to lysosome damage
Effective lysosome function is essential for health, and declines with ageing and disease. Upon lysosome damage, cells mount a complex stress response to restore homeostasis. Membrane ATG8ylation plays a central role, orchestrating lysosome repair, replacement and removal, either directly at the damaged membrane, via CASM (conjugation of ATG8s to single membranes), or at nascent autophagosomes, during lysophagy. Here, we identify a novel role for CASM in driving an antioxidant response to lysosome stress. Following damage, CASM regulates both lysosome ubiquitination and p62 recruitment. Membrane-associated p62 undergoes S349-phosphorylation, which permits KEAP1 sequestration, thereby releasing master transcription factor, NRF2. Liberated NRF2 translocates to the nucleus and promotes transcription of antioxidant and detoxifying genes, co-ordinating a cytoprotective response, in a CASM-dependent manner. These findings position CASM as a major upstream response to lysosome stress and uncover the p62/KEAP1/NRF2 axis as a novel effector pathway, termed SOLAR (SQSTM1/p62 Oligomer-mediated lysosome antioxidant response). HighlightsO_LICASM recruits p62/SQSTM1 as an effector protein during lysosome damage C_LIO_LICASM acts upstream to enhance ubiquitination of damaged lysosomes C_LIO_LICASM-recruited p62 engages KEAP1/NRF2 to drive antioxidant gene transcription (SOLAR) C_LI