Hyperactive Vps21 drives class E compartments

During endosomal maturation, transmembrane proteins targeted for lysosomal degradation are sorted into intralumenal vesicles (ILVs) by endosomal sorting complexes required for transport (ESCRTs). ESCRT dysfunction blocks ILV budding and induces the formation of aberrant stacks of flattened endosomal cisternae called class E compartments. The origin of these compartments is a long-standing mystery, but now Greg Odorizzi and co-workers (p. 5208) suggest that they form in the yeast Saccharomyces cerevisiae because of hyperactivity of Vps21, the yeast orthologue of the Rab5A GTPase that promotes early endosomal fusion activity in metazoans. The authors show that the formation of class E compartments requires Vps21, and that the compartments accumulate GTP-bound Vps21 and its effector CORVET (an endosomal tethering complex). E compartments also accumulate Ypt7, the yeast orthologue of Rab7 (which promotes the fusion of late endosomes with lysosomes in metazoans), but do not accumulate the Ypt7 effector HOPS (a tethering complex that is homologous to CORVET). Given these results, the authors suggest that ESCRT dysfunction causes the failure of the Rab5–Rab7 conversion that is thought to guide endosomal maturation, which results in Vps21 hyperactivity that drives the class E compartment morphology.