Fig. 6.

Schematic depicting the Ca²⁺-triggered endolysosomal membrane repair model. A cartoon representation of Ca²⁺-triggered endolysosomal membrane repair by ESCRT-III machinery mediated by ALIX (A) or ESCRT-I/II (B). The endolysosomal membrane damage leads to Ca²⁺ efflux from the endolysosome into the cytoplasm (A and B; 1), which leads to the membrane recruitment of the Ca²⁺ binding protein ALG-2 (A and B; 2). The membrane-recruited ALG-2 leads to downstream recruitment of ESCRT-III proteins via two parallel pathways: the ALIX pathway (A; 3 and 4) and the canonical ESCRT-I/II pathway (B; 3 and 4). The assembled ESCRT-III machinery forms a higher-order structure that can bring the open ends of the damaged membrane together (A and B; 5). Finally, remodeling of ESCRT-III filaments by AAA⁺ ATPase VPS4B drives membrane closure and repair.