Editors' ChoiceCell Biology

TACE Trafficking

Sci. Signal.  17 Jan 2012:
Vol. 5, Issue 207, pp. ec21
DOI: 10.1126/scisignal.2002847

The cytokine tumor necrosis factor (TNF) is a major driver of inflammation and contributes to the immune pathology seen in a variety of diseases, including inflammatory bowel disease, rheumatoid arthritis, and sepsis. Soluble TNF is produced by cleavage of its ectodomain by the ADAM family metalloprotease, TACE. However, the molecular regulation of TACE is not understood (see the Perspective by Lichtenthaler). Adrain et al. and McIlwain et al. now show that the rhomboid family member iRhom2 interacts with TACE in macrophages and is required for its proper intracellular trafficking and activation. In the absence of iRhom2, TACE was not released from the endoplasmic reticulum and active protease did not reach the cell surface. Because of an inability to produce TNF, iRhom2-deficient mice were more resistant to lipopolysaccharide-induced septic shock but could not adequately control a Listeria monocytogenes infection.

C. Adrain, M. Zettl, Y. Christova, N. Taylor, M. Freeman, Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE. Science 335, 225–228 (2012). [Abstract] [Full Text]

D. R. McIlwain, P. A. Lang, T. Maretzky, K. Hamada, K. Ohishi, S. K. Maney, T. Berger, A. Murthy, G. Duncan, H. C. Xu, K. S. Lang, D. Häussinger, A. Wakeham, A. Itie-Youten, R. Khokha, P. S. Ohashi, C. P. Blobel, T. W. Mak, iRhom2 regulation of TACE controls TNF-mediated protection against Listeria and responses to LPS. Science 335, 229–232 (2012). [Abstract] [Full Text]

S. F. Lichtenthaler, Sheddase gets guidance. Science 335, 179–180 (2012). [Abstract] [Full Text]