An ESCRT-III Polymerization Sequence Drives Membrane Deformation and Fission

TLDR

ESCRT‑III drives membrane fission from within membrane necks, a process essential for cell division, lysosome degradation, and autophagy, yet the mechanism of membrane breaking remains unknown. The study aims to characterize a sequential polymerization of ESCRT‑III subunits that, driven by a recruitment cascade and continuous subunit turnover powered by the ATPase Vps4, induces membrane deformation and fission. The authors show that ESCRT‑III subunits polymerize in a stepwise manner, with Vps4‑mediated turnover and a recruitment cascade, to deform membranes and drive fission. They find that exchanging Vps24 for Did2 tilts the polymer‑membrane interface, converting flat spirals into helical filaments that generate protrusions and culminate in a highly constricted Did2‑Ist1 co‑polymer capable of fission, supporting a stepwise filament‑structure change that drives ESCRT‑III activity.

Abstract

The endosomal sorting complex required for transport-III (ESCRT-III) catalyzes membrane fission from within membrane necks, a process that is essential for many cellular functions, from cell division to lysosome degradation and autophagy. How it breaks membranes, though, remains unknown. Here, we characterize a sequential polymerization of ESCRT-III subunits that, driven by a recruitment cascade and by continuous subunit-turnover powered by the ATPase Vps4, induces membrane deformation and fission. During this process, the exchange of Vps24 for Did2 induces a tilt in the polymer-membrane interface, which triggers transition from flat spiral polymers to helical filament to drive the formation of membrane protrusions, and ends with the formation of a highly constricted Did2-Ist1 co-polymer that we show is competent to promote fission when bound on the inside of membrane necks. Overall, our results suggest a mechanism of stepwise changes in ESCRT-III filament structure and mechanical properties via exchange of the filament subunits to catalyze ESCRT-III activity.