Trafficking, a key player in regulated intramembrane proteolysis

The term regulated intramembrane proteolysis (RIP) emerged from converging mechanisms aiming to release or activate signaling fragments or transcription factors from their respective membrane-anchored precursors. To date, four families of intramembrane proteases exist each of which process their own specific target substrates. As such, RIP initiates or abrogates a multitude of signaling cascades and plays a pivotal role in many physiological processes. The spatial and temporal localization of substrates versus proteases is of major importance in the diverse regulation of intramembrane proteolysis. Here we highlight the exciting conjunction between intracellular transport and RIP through the example of the routes taken by APP and its associated proteases.