Intramembrane proteases (IMP) are a paradigmatic class of proteolytic enzymes that are embedded in the lipid bilayer, where they cleave their transmembrane substrates. The potential of IMPs to become drug targets is underlined by the recent approval of the first IMP inhibitor, Nirogacestat, for rare tumors. The serine subclass of IMPs, also called rhomboid proteases, are the most ubiquitous IMPs in nature and are involved in several debilitating human diseases, including cancer or neurodegeneration. We mainly focus on the human rhomboids located in the secretory pathway and termed RHBDL1-4.

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