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Science 335 (6065): 225-228

Copyright © 2012 by the American Association for the Advancement of Science

Tumor Necrosis Factor Signaling Requires iRhom2 to Promote Trafficking and Activation of TACE

Colin Adrain,1,{dagger} Markus Zettl,1,*,{dagger} Yonka Christova,1 Neil Taylor,2 Matthew Freeman1,{ddagger}

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.

1 Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
2 Cambridge Research Institute, Cancer Research UK, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.

* Present address: Boehringer Ingelheim, NBE Discovery, Dr. Boehringer-Gasse 5-11, A-1121 Wien, Austria.

{dagger} These authors contributed equally to this work.

{ddagger} To whom correspondence should be addressed. E-mail: MF1{at}mrc-lmb.cam.ac.uk

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