Clipping or Extracting: Two Ways to Membrane Protein Degradation

Trends Cell Biol. 2015 Oct;25(10):611-622. doi: 10.1016/j.tcb.2015.07.003.


Protein degradation is a fundamentally important process that allows cells to recognize and remove damaged protein species and to regulate protein abundance according to functional need. A fundamental challenge is to understand how membrane proteins are recognized and removed from cellular organelles. While most of our understanding of this mechanism comes from studies on p97/Cdc48-mediated protein dislocation along the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway, recent studies have revealed intramembrane proteolysis to be an additional mechanism that can extract transmembrane segments. Here, we review these two principles in membrane protein degradation and discuss how intramembrane proteolysis, which introduces an irreversible step in protein dislocation, is used to drive regulated protein turnover.

Keywords: AAA-ATPase p97/VCP/Cdc48; endoplasmic reticulum-associated protein degradation; intramembrane proteolysis/protease; organellar protein homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism*
  • Animals
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum-Associated Degradation / genetics*
  • Humans
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Proteasome Endopeptidase Complex
  • Proteolysis*
  • Ubiquitin / genetics
  • Valosin Containing Protein


  • Cell Cycle Proteins
  • Membrane Proteins
  • Ubiquitin
  • Proteasome Endopeptidase Complex
  • Adenosine Triphosphatases
  • VCP protein, human
  • Valosin Containing Protein