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Cell Rep. 2014 Jun 26;7(6):1796-808. doi: 10.1016/j.celrep.2014.05.008. Epub 2014 May 29.

XIAP restricts TNF- and RIP3-dependent cell death and inflammasome activation.

Author information

1
III. Medizinische Klink, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
2
Research Unit Gene Vectors, Helmholtz Zentrum München-German Research Center for Environmental Health, GmbH, 85764 Oberschleissheim, Germany.
3
Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
4
Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
5
Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
6
Institute of Virology, Technische Universität München and Helmholtz Zentrum München, 81675 München, Germany.
7
Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland.
8
The Walter and Eliza Hall Institute of Medical Research, Parkville,VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
9
III. Medizinische Klink, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany. Electronic address: philipp.jost@lrz.tum.de.

Abstract

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-1β secretion from dendritic cells triggered by diverse Toll-like receptor stimuli. Aberrant IL-1β 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-1β secretion in response to TNF, which might contribute to hyperinflammation in patients with XLP-2.

PMID:
24882010
DOI:
10.1016/j.celrep.2014.05.008
[Indexed for MEDLINE]
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