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Zettl, M, Adrain, C, Strisovsky, K, Lastun, V and Freeman, M (2011) Rhomboid family pseudoproteases use the ER quality control machinery to regulate intercellular signaling. Cell 145:79-91

Intramembrane proteolysis governs many cellular control processes, but little is known about how intramembrane proteases are regulated. iRhoms are a conserved subfamily of proteins related to rhomboid intramembrane serine proteases that lack key catalytic residues. We have used a combination of genetics and cell biology to determine that these "pseudoproteases" inhibit rhomboid-dependent signaling by the epidermal growth factor receptor pathway in Drosophila, thereby regulating sleep. iRhoms prevent the cleavage of potential rhomboid substrates by promoting their destabilization by endoplasmic reticulum (ER)-associated degradation; this mechanism has been conserved in mammalian cells. The exploitation of the intrinsic quality control machinery of the ER represents a new mode of regulation of intercellular signaling. Inactive cognates of enzymes are common, but their functions are mostly unclear; our data indicate that pseudoenzymes can readily evolve into regulatory proteins, suggesting that this may be a significant evolutionary mechanism.

PubMed PMC3149277 Online version:10.1016/j.cell.2011.02.047

Animals; Drosophila/cytology; Drosophila/metabolism; Drosophila Proteins/chemistry; Drosophila Proteins/metabolism; Endoplasmic Reticulum/metabolism; Evolution, Molecular; Membrane Proteins/chemistry; Peptide Hydrolases/genetics; Peptide Hydrolases/metabolism; Proteins/metabolism; Receptor, Epidermal Growth Factor/metabolism; Serine Endopeptidases; Signal Transduction