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Intramembrane proteases catalyze the unusual cleavage of peptide bonds in the plane of biological membranes. They are categorized according to their active site. The GxGD aspartyl proteases comprise presenilin and the signal peptide peptidase (SPP), and SPP-like (SPPL) proteases. Here we focus on the functionally related SPP and SPPL proteases and review the current understanding of their substrate specificity and summarize known physiological functions in mammalian cells. We discuss how on one side regulated intramembrane proteolysis (RIP) generates signaling molecules and on the other side how processes, such as regulatory Endoplasmic Reticulum-associated degradation (ERAD-R) controls the quantity and activity of central regulators. While the enzymatic core of GxGD intramembrane proteases is conserved, association with regulatory factors and substrate adaptors may have tailored enzymes for various specific functions. Copyright © 2020. Published by Elsevier Ltd.
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