Regulated intramembrane proteolysis: from the endoplasmic reticulum to the nucleus

Regulated intramembrane proteolysis (Rip) is an ancient and widespread process by which cells transmit information from one compartment (the endoplasmic reticulum) to another (the nucleus). Two separate cleavages that are carried out by two separate proteases are required for Rip. The first protease cleaves its protein substrate within an extracytoplasmic domain; the second cleaves it within a membrane-spanning domain, releasing a functionally active fragment of the target protein. In eukaryotes, examples of Rip can be divided into two classes, according to the proteases that are involved and the orientation of the substrates with the membrane. Class 1 Rip involves type 1 transmembrane proteins and requires presenilin for cleavage within a membrane-spanning domain. In Class 2 Rip, the highly hydrophobic metalloprotease, site-2 protease, is required for cleavage within a membrane-spanning domain and substrates are type 2 transmembrane proteins. Both classes of Rip are implicated in diseases that are important in modern societies, such as hyperlipidaemias (via the sterol regulatory element binding protein pathway) and Alzheimer's disease (via processing of the amyloid precursor protein.)