TY - JOUR TI - FRMD8 promotes inflammatory and growth factor signalling by stabilising the iRhom/ADAM17 sheddase complex AU - Künzel, Ulrike AU - Grieve, Adam Graham AU - Meng, Yao AU - Sieber, Boris AU - Cowley, Sally A AU - Freeman, Matthew A2 - Burd, Christopher G VL - 7 PY - 2018 DA - 2018/06/13 SP - e35012 C1 - eLife 2018;7:e35012 DO - 10.7554/eLife.35012 UR - https://doi.org/10.7554/eLife.35012 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 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. KW - iRhom KW - rhomboid KW - inflammation KW - ADAM17 JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -