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The cytokine tumor necrosis factor (TNF) is the primary trigger of inflammation. Like many extracellular signaling proteins, TNF is synthesized as a transmembrane protein; the active signal is its ectodomain, which is shed from cells after cleavage by an ADAM family metalloprotease, ADAM17 (TNFα-converting enzyme, TACE). We report that iRhom2 (RHBDF2), a proteolytically inactive member of the rhomboid family, is required for TNF release in mice. iRhom2 binds TACE and promotes its exit from the endoplasmic reticulum. The failure of TACE to exit the endoplasmic reticulum in the absence of iRhom2 prevents the furin-mediated maturation and trafficking of TACE to the cell surface, the site of TNF cleavage. Given the role of TNF in autoimmune and inflammatory diseases, iRhom2 may represent an attractive therapeutic target.

Original publication

DOI

10.1126/science.1214400

Type

Journal article

Journal

Science

Publication Date

13/01/2012

Volume

335

Pages

225 - 228

Keywords

ADAM Proteins, ADAM17 Protein, Animals, Carrier Proteins, Cell Line, Cell Membrane, Endoplasmic Reticulum, Enzyme Activation, Furin, Humans, Lipopolysaccharides, Macrophages, Mice, Mice, Knockout, Protein Binding, Protein Transport, Signal Transduction, Tumor Necrosis Factor-alpha