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Publication

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

eLife | 2018

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 the iRhom2/ADAM17 sheddase complex. FRMD8 binds to the cytoplasmic N-terminus of iRhoms and is necessary to stabilise 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.

Pubmed ID: 29897336 RIS Download

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Associated grants

Agency: Wellcome Trust, United Kingdom
Id: 101035/Z/13/Z
Agency: Medical Research Council, United Kingdom
Id: MR/L023784/1
Agency: Medical Research Council, United Kingdom
Id: 1374214
Agency: Marie Curie, United Kingdom
Id: 659166
Agency: Medical Research Council, United Kingdom
Id: MR/M024962/1
Agency: NIH HHS, United States
Id: UM1 OD023221
Agency: Parkinson's UK, United Kingdom
Id: J-0901
Agency: Wellcome Trust, United Kingdom
Agency: Medical Research Council, United Kingdom
Id: MC_EX_MR/N50192X/1
Agency: Medical Research Council, United Kingdom
Id: MR/L023784/2
Agency: Wellcome Trust, United Kingdom
Id: Oxford Wellcome Institutional Strategic Support Fund 121302

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