Protein trafficking and maturation regulate intramembrane proteolysis

• Membrane trafficking regulates intramembrane proteolysis.
• Encounter between protease and its substrate is restricted by compartmentalization.
• Subcellular location of proteolysis affects cleavage site preference.
• Misregulated trafficking causes aberrant cleavage, implicated in several diseases.

Intramembrane-cleaving proteases (I-CLiPs) are membrane embedded proteolytic enzymes. All substrates identified so far are also membrane proteins, involving a number of critical cellular signaling as well as human diseases. After synthesis and assembly at the endoplasmic reticulum, membrane proteins are exported to the Golgi apparatus and transported to their sites of action. A number of studies have revealed the importance of the intracellular membrane trafficking in i-CLiP-mediated intramembrane proteolysis, not only for limiting the unnecessary encounter between i-CLiPs and their substrate but also for their cleavage site preference. In this review, we will discuss recent advances in our understanding of how each i-CLiP proteolysis is regulated by intracellular vesicle trafficking. This article is part of a Special Issue entitled: Intramembrane Proteases.

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