The complex life of rhomboid pseudoproteases

다국어 초록 (Multilingual Abstract)

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.
Rhomboid pseudoproteases are catalytically inactive members of the rhomboid superfamily. The founding members, rhomboids, were first identified in Drosophila as serine intramembrane proteases that cleave transmembrane proteins, enabling signaling. This led to the discovery of the wider rhomboid superfamily, a clan that in metazoans is dominated by pseudoproteases. These so‐called rhomboid pseudoproteases inherited from their catalytically active ancestors a conserved rhomboid‐like domain and a propensity to regulate signaling. Lacking catalytic activity, they developed new ‘pseudoenzyme’ functions that include regulating the trafficking, turnover, and activity of their client proteins. Rhomboid pseudoproteases have preeminent roles in orchestrating immune cell activation, antiviral responses, and cytokine release in response to microbial infection, or in chronic diseases, and have also been implicated in growth factor signaling, cancer, and, more recently, metabolism. Here, we discuss the mechanism(s) of action of rhomboid pseudoproteases, contrasted with rhomboid proteases. We also highlight the roles of rhomboid pseudoproteases in mammalian physiology, which, quite paradoxically among pseudoenzymes, is understood much better than active rhomboids.