Phosphorylation of iRhom2 at the plasma membrane controls mammalian TACE-dependent inflammatory and growth factor signalling

• DOI: 10.7554/elife.23968
• Publication Date: 2017-04-22T12:00:25Z
• Authors: Adam Graham Grieve; Hongmei Xu; Ulrike Künzel; Paul Bambrough; Boris Sieber; Matthew Freeman
• Keywords: 0301 basic medicine; 570; QH301-705.5; Science; 610; Carrier Proteins/metabolism; Macrophages/immunology; ADAM17 Protein; Biochemistry; Mice; 03 medical and health sciences; rhomboid; ADAM17 Protein/metabolism; growth factors; Animals; signalling; Biology (General); Phosphorylation; Protein Processing; TACE; Cell Membrane/metabolism; Macrophages; Q; Cell Membrane; Post-Translational; R; iRhom; 3. Good health; inflammation; Medicine; Carrier Proteins; Protein Processing, Post-Translational; Protein Binding; Signal Transduction

Proteolytic cleavage and release from the cell surface of membrane-tethered ligands is an important mechanism regulating intercellular signalling. TACE a major shedding protease, responsible for liberation inflammatory cytokine TNFα epidermal growth factor receptor. iRhoms, catalytically inactive members rhomboid-like superfamily, have been shown to control ER-to-Golgi transport maturation TACE. Here, we reveal that iRhom2 remains associated with throughout secretory pathway, stabilised at by this interaction. At plasma membrane, ERK1/2-mediated phosphorylation 14-3-3 protein binding cytoplasmic amino-terminus alter its interaction mature TACE, thereby licensing proteolytic activity. We show molecular triggering responses in primary mouse macrophages. Overall, binds lifecycle, implying regulator stimulated