Clipping or Extracting: Two Ways to Membrane Protein Degradation

Degradation of damaged and surplus membrane proteins ensures the functionality of cellular membranes. Extraction of membrane integral proteins from the lipid bilayer needs to overcome a high activation barrier. Accurate substrate selection and their efficient turnover are important to sustain membrane protein homeostasis. Recent studies showed that intramembrane proteolysis of transmembrane anchors provides an additional release mechanism to dislocation of full-length proteins by AAA-ATPases, such as p97/Cdc48. Intramembrane cleavage serves as an irreversible step in membrane protein degradation, providing a level of regulation. A redundant set of dislocases and intramembrane proteases work together to control the cellular membrane proteome. 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. 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.