Link between lipid remodeling and ESCRT-III function in multivesicular body formation

Abstract

Despite a tremendous amount of work, it is still unclear how the endosomal sorting complex required for transport (ESCRT)-III complex acts in membrane remodeling and abscission. Here we present evidence that a change in membrane composition is connected to ESCRT-III function during multivesicular body (MVB) formation. The central observation was a strong synergistic effect of two mutations on the turnover of an endocytic cargo protein. One mutation deletes Tms1, a yeast SERINC homologue. Human SERINC3 and SERINC5 are HIV-1 restriction factors and have been shown to act as scramblases, flipping phospholipids between membrane leaflets. The other mutation deletes the Vps68 subunit of the Vps55/Vps68 complex, which loosely resembles Tms1 in its overall structure. The strong synergistic effect suggests that Tms1 and Vps55/Vps68 perform a similar function. Since we could also show that Vps55 physically interacts with ESCRT-III, we propose that a scramblase is recruited to ESCRT-III and prepares the membrane for intraluminal vesicles formation at MVBs.SummaryIt is still unclear how ESCRT-III acts on membranes. Here evidence is presented that ESCRT-III recruits a scramblase to the site of intraluminal vesicle formation at late endosomes indicating that a change in membrane composition is crucial for MVB formation.