iRhom2 regulation of TACE controls TNF-mediated protection against Listeria and responses to LPS |
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Authors: | McIlwain David R Lang Philipp A Maretzky Thorsten Hamada Koichi Ohishi Kazuhito Maney Sathish Kumar Berger Thorsten Murthy Aditya Duncan Gordon Xu Haifeng C Lang Karl S Häussinger Dieter Wakeham Andrew Itie-Youten Annick Khokha Rama Ohashi Pamela S Blobel Carl P Mak Tak W |
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Affiliation: | Campell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network (UHN), 620 University Avenue, Toronto, Ontario M5G 2C1, Canada. |
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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. |
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