A Translocation Pathway for Vesicle-Mediated Unconventional Protein Secretion

Cell. 2020 Apr 30;181(3):637-652.e15. doi: 10.1016/j.cell.2020.03.031. Epub 2020 Apr 8.


Many cytosolic proteins lacking a signal peptide, called leaderless cargoes, are secreted through unconventional secretion. Vesicle trafficking is a major pathway involved. It is unclear how leaderless cargoes enter into the vesicle. Here, we find a translocation pathway regulating vesicle entry and secretion of leaderless cargoes. We identify TMED10 as a protein channel for the vesicle entry and secretion of many leaderless cargoes. The interaction of TMED10 C-terminal region with a motif in the cargo accounts for the selective release of the cargoes. In an in vitro reconstitution assay, TMED10 directly mediates the membrane translocation of leaderless cargoes into the liposome, which is dependent on protein unfolding and enhanced by HSP90s. In the cell, TMED10 localizes on the endoplasmic reticulum (ER)-Golgi intermediate compartment and directs the entry of cargoes into this compartment. Furthermore, cargo induces the formation of TMED10 homo-oligomers which may act as a protein channel for cargo translocation.

Keywords: ER-Golgi intermediate compartment; Galectin; HSP90; HSPB5; TMED10; inflammation; interleukin-1; membrane trafficking; translocation; unconventional protein secretion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport
  • Cell Line
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Cytosol / metabolism
  • Endoplasmic Reticulum / metabolism
  • Golgi Apparatus / metabolism
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Protein Sorting Signals
  • Protein Translocation Systems / metabolism*
  • Protein Translocation Systems / physiology
  • Protein Transport / physiology
  • Proteins / metabolism
  • Secretory Pathway
  • Vesicular Transport Proteins / metabolism*
  • Vesicular Transport Proteins / physiology


  • Protein Sorting Signals
  • Protein Translocation Systems
  • Proteins
  • Tmed10 protein, mouse
  • Vesicular Transport Proteins