期刊
CELL REPORTS
卷 7, 期 6, 页码 1796-1808出版社
CELL PRESS
DOI: 10.1016/j.celrep.2014.05.008
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资金
- Deutsche Krebshilfe [109310]
- Human Frontiers Science Program grant [RGY0073/2012]
- German Jose Carreras Leukemia Foundation [DJCLS R 12/22]
- Wilhelm Sander-Stiftung [2009.046.1+2]
- BMBF (NGFNplus) [PIM-01GS0802-3]
- Helmholtz-Foundation
- Peter-Hans Hofschneider Foundation
- Natural Science and Engineering Research Council of Canada
- Bavarian Molecular Biosystems Research Network
- Steno Fellowship from the Danish Council for Independent Research-Natural Sciences
- Lundbeck Foundation
- Novo Nordisk Foundation
X-linked inhibitor of apoptosis protein (XIAP) has been identified as a potent regulator of innate immune responses, and loss-of-function mutations in XIAP cause the development of the X-linked lymphoproliferative syndrome type 2 (XLP-2) in humans. Using gene-targeted mice, we show that loss of XIAP or deletion of its RING domain lead to excessive cell death and IL-1 beta secretion from dendritic cells triggered by diverse Toll-like receptor stimuli. Aberrant IL-1 beta secretion is TNF dependent and requires RIP3 but is independent of cIAP1/cIAP2. The observed cell death also requires TNF and RIP3 but proceeds independently of caspase-1/caspase-11 or caspase-8 function. Loss of XIAP results in aberrantly elevated ubiquitylation of RIP1 outside of TNFR complex I. Virally infected Xiap(-/-) mice present with symptoms reminiscent of XLP-2. Our data show that XIAP controls RIP3-dependent cell death and IL-1 beta secretion in response to TNF, which might contribute to hyperinflammation in patients with XLP-2.
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