An ER-Associated Pathway Defines Endosomal Architecture for Controlled Cargo Transport

TLDR

The endosomal system forms a bilaterally organized network of progressively maturing vesicles, comprising a relatively immobile perinuclear vesicle cloud and a highly dynamic peripheral contingent, whose spatiotemporal organization and functions remain unclear. RNF26, an ER‑localized ubiquitin ligase, specifies perinuclear vesicle coordinates by ubiquitinating the scaffold p62/SQSTM1, recruiting ubiquitin‑binding domains of vesicle adaptors, and restraining fast vesicle transport until the deubiquitinase USP15 counteracts RNF26 to release vesicles to the periphery. RNF26 thereby orchestrates endosomal maturation and spatially and temporally regulates trafficking of cargoes, including signaling receptors, across the endosomal system.

Abstract

Through a network of progressively maturing vesicles, the endosomal system connects the cell's interior with extracellular space. Intriguingly, this network exhibits a bilateral architecture, comprised of a relatively immobile perinuclear vesicle "cloud" and a highly dynamic peripheral contingent. How this spatiotemporal organization is achieved and what function(s) it curates is unclear. Here, we reveal the endoplasmic reticulum (ER)-located ubiquitin ligase Ring finger protein 26 (RNF26) as the global architect of the entire endosomal system, including the trans-Golgi network (TGN). To specify perinuclear vesicle coordinates, catalytically competent RNF26 recruits and ubiquitinates the scaffold p62/sequestosome 1 (p62/SQSTM1), in turn attracting ubiquitin-binding domains (UBDs) of various vesicle adaptors. Consequently, RNF26 restrains fast transport of diverse vesicles through a common molecular mechanism operating at the ER membrane, until the deubiquitinating enzyme USP15 opposes RNF26 activity to allow vesicle release into the cell's periphery. By drawing the endosomal system's architecture, RNF26 orchestrates endosomal maturation and trafficking of cargoes, including signaling receptors, in space and time.