Triggered recruitment of ESCRT machinery promotes endolysosomal repair

TLDR

Endolysosomes can be damaged by diverse materials, and while terminally damaged compartments are degraded by lysophagy, repair pathways for salvageable organelles remain poorly understood. ESCRT complexes are rapidly recruited to acutely injured endolysosomes through a calcium‑dependent, ESCRT‑activating factor pathway independent of lysophagy, and live‑cell imaging shows they respond to small perforations and enable recovery from limited damage. ESCRT machinery is essential for repairing endolysosomes, being recruited by silica crystal disruption and other insults, thereby providing a defense against endolysosomal damage relevant in physiological and pathological contexts.

Abstract

Endolysosomes can be damaged by diverse materials. Terminally damaged compartments are degraded by lysophagy, but pathways that repair salvageable organelles are poorly understood. Here we found that the endosomal sorting complex required for transport (ESCRT) machinery, known to mediate budding and fission on endolysosomes, also plays an essential role in their repair. ESCRTs were rapidly recruited to acutely injured endolysosomes through a pathway requiring calcium and ESCRT-activating factors that was independent of lysophagy. We used live-cell imaging to demonstrate that ESCRTs responded to small perforations in endolysosomal membranes and enabled compartments to recover from limited damage. Silica crystals that disrupted endolysosomes also triggered ESCRT recruitment. ESCRTs thus provide a defense against endolysosomal damage likely to be relevant in physiological and pathological contexts.