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

Markus Zettl, Colin Adrain, Kvido Strisovsky, Viorica Lastun, Matthew Freeman

Research output: Contribution to journalArticlepeer-review

123 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)79-91
Number of pages13
Issue number1
Publication statusPublished - 01 Apr 2011

Bibliographical note

Copyright © 2011 Elsevier Inc. All rights reserved.


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


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