FRMD8 promotes inflammatory and growth factor signalling by stabilising the iRhom/ADAM17 sheddase complex

  1. Ulrike Künzel
  2. Adam Graham Grieve
  3. Yao Meng
  4. Boris Sieber
  5. Sally A Cowley
  6. Matthew Freeman  Is a corresponding author
  1. University of Oxford, United Kingdom

Abstract

Many intercellular signals are synthesised as transmembrane precursors that are released by proteolytic cleavage ('shedding') from the cell surface. ADAM17, a membrane-tethered metalloprotease, is the primary shedding enzyme responsible for the release of the inflammatory cytokine TNFα and several EGF receptor ligands. ADAM17 exists in complex with the rhomboid-like iRhom proteins, which act as cofactors that regulate ADAM17 substrate shedding. Here we report that the poorly characterised FERM domain-containing protein FRMD8 is a new component of iRhom2/ADAM17 sheddase complex. FRMD8 binds to the cytoplasmic N-terminus of iRhoms and is necessary to stabilise the iRhoms and ADAM17 at the cell surface. In the absence of FRMD8, iRhom2 and ADAM17 are degraded via the endolysosomal pathway, resulting in the reduction of ADAM17-mediated shedding. We have confirmed the pathophysiological significance of FRMD8 in iPSC-derived human macrophages and mouse tissues, thus demonstrating its role in the regulated release of multiple cytokine and growth factor signals.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Ulrike Künzel

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  2. Adam Graham Grieve

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  3. Yao Meng

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  4. Boris Sieber

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  5. Sally A Cowley

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0297-6675
  6. Matthew Freeman

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    For correspondence
    matthew.freeman@path.ox.ac.uk
    Competing interests
    Matthew Freeman, Reviewing editor, <i>eLife</i>.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0410-5451

Funding

Wellcome (101035/Z/13/Z)

  • Matthew Freeman

Medical Research Council (1374214)

  • Ulrike Künzel

Boehringer Ingelheim Fonds (PhD Fellowship)

  • Ulrike Künzel
  • Boris Sieber

Horizon 2020 Framework Programme (659166)

  • Adam Graham Grieve

Medical Research Council (MC_EX_MR/N50192X/1)

  • Sally A Cowley

Wellcome (Oxford Wellcome Institutional Strategic Support Fund 121302)

  • Sally A Cowley

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Human iPSC lines were derived from dermal fibroblasts of donors that had given signed informed consent for the derivation of human iPSC lines from skin biopsies and SNP analysis (Ethics Committee: National Health Service, Health Research Authority, NRES Committee South Central, Berkshire, UK (REC 10/H0505/71)). All procedures on mice were conducted in accordance with the UK Scientific Procedures Act (1986) under a project license (PPL) authorized by the UK Home Office Animal Procedures Committee, project licenses 80/2584 and 30/2306, and approved by the Sir William Dunn School of Pathology Local Ethical Review Committee.

Reviewing Editor

  1. Christopher G Burd, Yale School of Medicine, United States

Publication history

  1. Received: January 12, 2018
  2. Accepted: May 26, 2018
  3. Accepted Manuscript published: June 13, 2018 (version 1)
  4. Version of Record published: July 12, 2018 (version 2)

Copyright

© 2018, Künzel et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ulrike Künzel
  2. Adam Graham Grieve
  3. Yao Meng
  4. Boris Sieber
  5. Sally A Cowley
  6. Matthew Freeman
(2018)
FRMD8 promotes inflammatory and growth factor signalling by stabilising the iRhom/ADAM17 sheddase complex
eLife 7:e35012.
https://doi.org/10.7554/eLife.35012

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