FRMD8 promotes inflammatory and growth factor signalling by stabilising the iRhom/ADAM17 sheddase complex
- 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.
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Author details
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.
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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FRMD8 promotes inflammatory and growth factor signalling by stabilising the iRhom/ADAM17 sheddase complex
eLife 7:e35012.
https://doi.org/10.7554/eLife.35012
