Quantitative proteomics screen identifies a substrate repertoire of rhomboid protease RHBDL2 in human cells and implicates it in epithelial homeostasis

Nicholas Johnson, Jana Březinová, Elaine Stephens, Emma Burbridge, Matthew Freeman, Colin Adrain, Kvido Strisovsky

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Rhomboids are intramembrane serine proteases conserved in all kingdoms of life. They regulate epidermal growth factor receptor signalling in Drosophila by releasing signalling ligands from their transmembrane tethers. Their functions in mammals are poorly understood, in part because of the lack of endogenous substrates identified thus far. We used a quantitative proteomics approach to investigate the substrate repertoire of rhomboid protease RHBDL2 in human cells. We reveal a range of novel substrates that are specifically cleaved by RHBDL2, including the interleukin-6 receptor (IL6R), cell surface protease inhibitor Spint-1, the collagen receptor tyrosine kinase DDR1, N-Cadherin, CLCP1/DCBLD2, KIRREL, BCAM and others. We further demonstrate that these substrates can be shed by endogenously expressed RHBDL2 and that a subset of them is resistant to shedding by cell surface metalloproteases. The expression profiles and identity of the substrates implicate RHBDL2 in physiological or pathological processes affecting epithelial homeostasis.

Original languageEnglish
Pages (from-to)7283
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - 04 Aug 2017
Externally publishedYes

Keywords

  • ADAM10 Protein/metabolism
  • ADAM17 Protein/metabolism
  • Amino Acid Sequence
  • Binding Sites
  • Epithelial Cells/metabolism
  • Epithelium/metabolism
  • Homeostasis
  • Humans
  • Membrane Proteins/metabolism
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Proteolysis
  • Proteome
  • Proteomics/methods
  • Serine Proteases/genetics
  • Substrate Specificity

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