title: Rhomboid family pseudoproteases use the ER quality control machinery to regulate intercellular signaling.
abstract: 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.
authors: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
authors: Markus
authors: M
authors: Zettl
authors: Colin
authors: C
authors: Adrain
authors: Kvido
authors: K
authors: Strisovsky
authors: Viorica
authors: V
authors: Lastun
authors: Matthew
authors: M
authors: Freeman
mesh_terms: D000818:Animals; D004330:Drosophila / Q000166:cytology / Q000378:metabolism*; D029721:Drosophila Proteins / Q000737:chemistry / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D019143:Evolution, Molecular; D008565:Membrane Proteins / Q000737:chemistry; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D012697:Serine Endopeptidases; D015398:Signal Transduction
chemical_list: D029721:Drosophila Proteins; D008565:Membrane Proteins; D011506:Proteins; C081481:Rho protein, Drosophila; D066246:ErbB Receptors; D010447:Peptide Hydrolases; D012697:Serine Endopeptidases