ATG16L inhibits the lysosomal v-ATPase under normal conditions but leads to its activation in response to stress. Left: ATG16L binds to V1H of the v-ATPase under normal conditions, reducing lysosome acidification (red arrow). Inhibition by ATG16L may or may not involve CASM. Right: Under stress or damage, ATG16L-dependent CASM activation occurs with increased v-ATPase assembly through mRAVE (DMXL1/2, WDR7, and ROGDI). Increased acidification may necessitate ATG16L disengagement. Alternatively, different ATG8 effectors could mediate different effects on v-ATPase activity, potentially linked to conjugation of different ATG8 orthologs (depicted in grayscale), and attachment to either phosphatidylserine or phosphatidylethanolamine (PS/PE). Note: mRAVE is depicted on a v-ATPase holoenzyme but may disengage after assembly, and ATG16L and mRAVE binding to the v-ATPase may be mutually exclusive. Figure created on https://Biorender.com.