The ALS- and FTD-associated proteins Annexin A11 and CHMP2B act sequentially in membrane repair

Maintenance of plasma membrane and organellar integrity is essential for cell viability. Cells must recognise damaged membranes and orchestrate repair programmes to preserve compartmentalisation. A variety of cellular factors including ESCRTs, Annexins, stress granules, lipids and proteins allowing vesicle and organelle fusion with damaged membranes have been reported to contribute to membrane repair. However, whether these factors operate independently or together to repair membranes is unclear. Here, we expose temporal differences and interdependencies in the recruitment of ESCRT-III and Annexin proteins to sites of membrane damage. We show that while Annexins are recruited immediately to sites of damage, ESCRT-III assembles only after membrane sealing. We show that ESCRT-III acts to shed damaged membranes from the cell and that FTD-and ALS-associated mutations in CHMP2B and ANXA11 compromise the repair process. These data present an integrated sealing and healing model of events allowing membrane repair and restoration of membrane integrity. One-Sentence Summary: A rubric of sealing and healing for ESCRT-mediated membrane repair