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Science 335 (6065): 229-232

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

iRhom2 Regulation of TACE Controls TNF-Mediated Protection Against Listeria and Responses to LPS

David R. McIlwain,1,2,* Philipp A. Lang,1,3,* Thorsten Maretzky,4 Koichi Hamada,5 Kazuhito Ohishi,6 Sathish Kumar Maney,3 Thorsten Berger,1 Aditya Murthy,7 Gordon Duncan,1 Haifeng C. Xu,1,3 Karl S. Lang,3,8 Dieter Häussinger,3 Andrew Wakeham,1 Annick Itie-Youten,1 Rama Khokha,7 Pamela S. Ohashi,1,2 Carl P. Blobel,4,9 Tak W. Mak1,2,{dagger}

Abstract: Innate immune responses are vital for pathogen defense but can result in septic shock when excessive. A key mediator of septic shock is tumor necrosis factor–α (TNFα), which is shed from the plasma membrane after cleavage by the TNFα convertase (TACE). We report that the rhomboid family member iRhom2 interacted with TACE and regulated TNFα shedding. iRhom2 was critical for TACE maturation and trafficking to the cell surface in hematopoietic cells. Gene-targeted iRhom2-deficient mice showed reduced serum TNFα in response to lipopolysaccharide (LPS) and could survive a lethal LPS dose. Furthermore, iRhom2-deficient mice failed to control the replication of Listeria monocytogenes. Our study has identified iRhom2 as a regulator of innate immunity that may be an important target for modulating sepsis and pathogen defense.

1 Campell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network (UHN), 620 University Avenue, Toronto, Ontario M5G 2C1, Canada.
2 Department of Medical Biophysics, University of Toronto, 1 King's Circle, Toronto, Ontario M5S 1A8, Canada.
3 Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
4 Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA.
5 Okada Projects at the Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan.
6 Department of Pathology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
7 Ontario Cancer Institute, UHN, Toronto, Ontario, M5G 2M9, Canada.
8 Institute for Immunology, University of Essen, Hufelandstrasse 55, 45147 Essen, Germany
9 Departments of Medicine and of Physiology, Biophysics and Systems Biology, Weill Medical College of Cornell University, New York, NY 10021, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: tmak{at}uhnresearch.ca

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