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Cited by 54Protease and Inhibitor MechanismsBlood Coagulation and Thrombosis MechanismsUbiquitin and proteasome pathways

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

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Johnson, Nicholas, Březinová, Jana, Stephens, Elaine, Burbridge, Emma, Freeman, Matthew, Adrain, Colin, Strisovsky, Kvido·2017·Scientific Reports
DOI 10.1038/s41598-017-07556-3PMC PMC5544772
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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.

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  • The missense variant rs72938840 (Arg59Gln, MAF AFR = 7.9%) in RHBDL2 is associated in trans with concentrations of SPINT1 (P = 5.8 × 10 -12).

    “The missense variant rs72938840 (Arg59Gln, MAF AFR = 7.9%) in the gene encoding rhomboid protease, RHBDL2, is mostly absent in EUR and other ancestries 28 and is associated in trans with concentrations of one of its cleavage substrates 29 , SPINT1 (P = 5.8 × 10 -12 )”

    From Plasma proteomic associations with genetics and health in the UK Biobank (2023) · cites this paper as [29]

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Authors
Johnson, N., Březinová, J., Stephens, E., Burbridge, E., Freeman, M., Adrain, C., & Strisovsky, K.
Affiliations
  • Czech Academy of Sciences (CZ)
  • MRC Laboratory of Molecular Biology (GB)
  • Instituto Gulbenkian de Ciência (PT)
Corresponding author
Adrain, Colin
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2017-08-04
Volume
7
Issue
1
Pages
7283-7283
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-017-07556-3
PMC
PMC5544772
OpenAlex
W2741610891
Cited by
54
References
0
Citations by year
2026: 4 · 2025: 5 · 2024: 7 · 2023: 3 · 2022: 5 · 2021: 10 · 2020: 6 · 2019: 8 · 2018: 6
FWCI
1.84
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
  • ASEP (submittedVersion, public-domain)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Wellcome Trust (101035/Z/13/Z, 101035)
  • European Commission (304154, 618769)
  • Akademie Věd České Republiky (61388963)
  • Medical Research Council (MC_U105178780)
  • Fundação para a Ciência e a Tecnologia (BM1406, BEX-BCM/3015/2014, PTDC/BEX-BCM/3015/2014)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
rhomboid protease, intramembrane serine proteases, substrate identification, epithelial homeostasis, IL-6 receptor, DDR1, N-cadherin, BCAM
MeSH terms
ADAM10 Protein, ADAM17 Protein, Amino Acid Sequence, Binding Sites, Epithelial Cells, Epithelium, Homeostasis, Humans, Membrane Proteins, Protein Binding, Serine Endopeptidases, Substrate Specificity, Proteome, Proteomics, Protein Interaction Domains and Motifs, Serine Proteases, Proteolysis

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