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Science 335 (6065): 179-180

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

Sheddase Gets Guidance

Stefan F. Lichtenthaler

Proteases that cleave at the surface of cells release the ectodomain of membrane proteins and control the communication between cells. One example is the cytokine tumor necrosis factor-α (TNFα), which is essential for innate immunity. It is cleaved by the metalloprotease TNFα-converting enzyme (TACE or ADAM17) (1, 2). Too much TNFα shedding, however, contributes to inflammatory diseases, which makes TACE an obvious drug target for conditions such as rheumatoid arthritis and sepsis. The generation of specific small-molecule TACE inhibitors has remained challenging, which has led to the search for alternative approaches to control its activity. Adrain et al. (3) and McIlwain et al. (4) report on pages 225 and 229 of this issue, respectively, that a protein called iRhom2 is essential for TACE to release TNFα from the cell surface. Mice lacking the iRhom2 gene secrete less TNFα and succumb to bacterial infection. The findings provide exciting links between intracellular protein trafficking, cell surface proteolysis, and inflammation.

DZNE—German Center for Neurodegenerative Diseases Munich, 80336 Munich, and Butenandt-Institute, University of Munich, 80336 Munich, Germany.

E-mail: stefan.lichtenthaler{at}

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