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

Ulrike Künzel,Adam Graham Grieve,Boris Sieber,Matthew Freeman,Sally A Cowley,Yao Meng

doi:10.7554/elife.35012

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 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.

Highlights

The cell surface protease ADAM17 mediates the release of many important signalling molecules by ‘shedding’ their extracellular ligand domains from transmembrane precursors
Among the hits were several 14-3-3 proteins and MAPK1/3 (Table 1), which we have previously reported to participate in the regulation of inflammatory signalling by phosphorylation of iRhom2 (Grieve et al, 2017)
We report that FERM domain-containing protein 8 (FRMD8) is a new component of the regulatory machinery that controls the release of ADAM17 substrates, including tumour necrosis factor alpha (TNFa)

Summary

Introduction

The cell surface protease ADAM17 ( called TACE) mediates the release of many important signalling molecules by ‘shedding’ their extracellular ligand domains from transmembrane precursors. We and others have previously reported that the rhomboid-like iRhom proteins have a specific and extensive regulatory relationship with ADAM17, to the extent that iRhoms can effectively be considered as regulatory subunits of the protease (Grieve et al, 2017). The family is named after the rhomboids, intramembrane serine proteases that cleave substrate transmembrane domains (TMDs), but many members, including iRhoms, have lost protease activity during evolution. IRhom and its paralogue iRhom (encoded by the genes RHBDF1 and RHBDF2) show redundancy in regulating ADAM17 maturation, but differ in their tissue expression (Christova et al, 2013). Macrophages are, an exception: iRhom is not expressed, so iRhom alone regulates ADAM17 and

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