The complex life of rhomboid pseudoproteases

Rhomboid proteases are serine proteases that cleave their substrates within transmembrane helices. Surprisingly, the metazoan rhomboid‐like family is dominated by the presence of rhomboid homologs that lack the residues essential for proteolytic catalysis found in their rhomboid protease counterparts. In spite of lacking proteolytic activity, these rhomboid pseudoproteases have emerged during the last decade to play critical roles in cell signaling, innate immunity, and protein quality control. Here, Adrain and Cavadas discuss the pathophysiological roles and mechanism of action of rhomboid pseudoproteases.