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Science. 2012 Jan 13;335(6065):225-8. doi: 10.1126/science.1214400.

Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE.

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1
Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.

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.

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PMID:
22246777
PMCID:
PMC3272371
DOI:
10.1126/science.1214400
[Indexed for MEDLINE]
Free PMC Article

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