The apical inflammatory cytokine TNF regulates numerous important biological processes including inflammation and cell death, and drives inflammatory diseases. TNF secretion requires TACE (also called ADAM17), which cleaves TNF from its transmembrane tether. The trafficking of TACE to the cell surface, and stimulation of its proteolytic activity, depends on membrane proteins, called iRhoms. To delineate how the TNF/TACE/iRhom axis is regulated, we performed an immunoprecipitation/mass spectrometry screen to identify iRhom-binding proteins. This identified a novel protein, that we name iTAP (iRhom Tail-Associated Protein) that binds to iRhoms, enhancing the cell surface stability of iRhoms and TACE, preventing their degradation in lysosomes. Depleting iTAP in primary human macrophages profoundly impaired TNF production and tissues from iTAP KO mice exhibit a pronounced depletion in active TACE levels. Our work identifies iTAP as a physiological regulator of TNF signalling and a novel target for the control of inflammation.

Center for Biological Systems Analysis Faculty of Biology Albert Ludwigs Universitaet Freiburg Freiburg Germany

Edinburgh Cancer Research UK Centre Institute of Genetics and Molecular Medicine University of Edinburgh Edinburgh United Kingdom

Institut für Analytische Chemie Universität Wien Vienna Austria

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic Prague Czech Republic

Membrane Traffic Lab Instituto Gulbenkian de Ciência Oeiras Portugal

Molecular Cell Biology Laboratory Department of Genetics The Smurfit Institute Trinity College Dublin Dublin Ireland

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A structural model of the iRhom-ADAM17 sheddase complex reveals functional insights into its trafficking and activity

The iRhom homology domain is indispensable for ADAM17-mediated TNFα and EGF receptor ligand release