Rhomboid family pseudoproteases use the ER quality control machinery to regulate intercellular signaling

Cell. 2011 Apr 1;145(1):79-91. doi: 10.1016/j.cell.2011.02.047.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Drosophila / cytology
  • Drosophila / metabolism*
  • Drosophila Proteins / chemistry
  • Drosophila Proteins / metabolism*
  • Endoplasmic Reticulum / metabolism*
  • ErbB Receptors / metabolism
  • Evolution, Molecular
  • Membrane Proteins / chemistry
  • Peptide Hydrolases / genetics
  • Peptide Hydrolases / metabolism*
  • Proteins / metabolism*
  • Serine Endopeptidases
  • Signal Transduction*


  • Drosophila Proteins
  • Membrane Proteins
  • Proteins
  • Rho protein, Drosophila
  • ErbB Receptors
  • Peptide Hydrolases
  • Serine Endopeptidases