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XIAP Restricts TNF- and RIP3-Dependent Cell Death and Inflammasome Activation


Yabal, M; Mueller, N; Adler, H; Knies, N; Thomas, CJ; Damgaard, RB; Kanegane, H; Ringelhan, M; Kaufmann, T; Heikenwaelder, M; Peschel, C; Strasser, A; Gross, O; Ruland, J; Gyrd-Hansen, M; Jost, PJ
2014-05-28
Cell Reports
Journal Article (Primary, Peer Reviewed)
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
Cell Press
Molecular Genetics of Cancer
10.1016/j.celrep.2014.05.008
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).