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Yabal, M.* ; Müller, N.* ; Adler, H. ; Knies, N.* ; Groß, C.J.* ; Damgaard, R.B.* ; Kanegane, H.* ; Ringelhan, M. ; Kaufmann, T.* ; Heikenwälder, M. ; Strasser, A.* ; Groß, O.* ; Ruland, J.* ; Peschel, C.* ; Gyrd-Hansen, M.* ; Jost, P.J.*

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

Cell Rep. 7, 1796-1808 (2014)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Nf-kappa-b; Linked Lymphoproliferative Syndrome; Alpha-dependent Apoptosis; Hemophagocytic Lymphohistiocytosis; Programmed Necrosis; Immune-response; Deficiency; Disease; Complex; Iaps
Language english
Publication Year 2014
HGF-reported in Year 2014
ISSN (print) / ISBN 2211-1247
e-ISSN 2211-1247
Journal Cell Reports
Quellenangaben Volume: 7, Issue: 6, Pages: 1796-1808 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place Cambridge
Reviewing status Peer reviewed
Institute(s) Research Unit Gene Vector (AGV)
Institute of Virology (VIRO)
POF-Topic(s) 30203 - Molecular Targets and Therapies
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s) Immune Response and Infection
PSP Element(s) G-501500-006
G-551600-001
PubMed ID 24882010
DOI 10.1016/j.celrep.2014.05.008
WOS ID WOS:000338325400006
Scopus ID 84903480849
Erfassungsdatum 2014-06-04
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