PT  - JOURNAL ARTICLE
AU  - Ulrike Künzel
AU  - Adam G. Grieve
AU  - Yao Meng
AU  - Sally A. Cowley
AU  - Matthew Freeman
TI  - FRMD8 promotes inflammatory and growth factor signalling by stabilising the iRhom/ADAM17 sheddase complex
AID  - 10.1101/255802
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 255802
4099  - http://biorxiv.org/content/early/2018/01/30/255802.short
4100  - http://biorxiv.org/content/early/2018/01/30/255802.full
AB  - 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 beyond the Golgi. 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.