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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.

Original publication

DOI

10.1016/j.celrep.2014.05.008

Type

Journal article

Journal

Cell reports

Publication Date

06/2014

Volume

7

Pages

1796 - 1808

Addresses

III. Medizinische Klink, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.

Keywords

Dendritic Cells, Animals, Mice, Transgenic, Mice, Lipopolysaccharides, Tumor Necrosis Factor-alpha, Cell Death, Apoptosis, Female, Male, X-Linked Inhibitor of Apoptosis Protein, Interleukin-1beta, Receptor-Interacting Protein Serine-Threonine Kinases, Inflammasomes