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

Cell. 2016 Jun 30;166(1):152-66. doi: 10.1016/j.cell.2016.05.078.


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.

Keywords: E3 ligase; EGFR signaling; EPS15; ER; RNF26; TAX1BP1; TGN; TOLLIP; USP15; endosomes; lysosomes; perinuclear; transport; ubiquitin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Dendritic Cells / cytology
  • Dendritic Cells / metabolism
  • Endoplasmic Reticulum / metabolism*
  • Endosomes / metabolism*
  • Humans
  • Intracellular Membranes / metabolism*
  • Macrophages / cytology
  • Macrophages / metabolism
  • Neoplasm Proteins / metabolism*
  • Sequestosome-1 Protein / metabolism
  • Transport Vesicles / metabolism
  • Ubiquitin-Specific Proteases / metabolism


  • Neoplasm Proteins
  • RNF26 protein, human
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • USP15 protein, human
  • Ubiquitin-Specific Proteases