title: Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE.
abstract: 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.
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Adrain
authors.forename: Markus
authors.initials: M
authors.lastname: Zettl
authors.forename: Yonka
authors.initials: Y
authors.lastname: Christova
authors.forename: Neil
authors.initials: N
authors.lastname: Taylor
authors.forename: Matthew
authors.initials: M
authors.lastname: Freeman
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004789:Enzyme Activation; D045683:Furin / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D021381:Protein Transport; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C569468:iRhom2 protein, mouse; D045683:Furin; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse