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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)
Verlagsversion Volltext DOI
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Nf-kappa-b; Linked Lymphoproliferative Syndrome; Alpha-dependent Apoptosis; Hemophagocytic Lymphohistiocytosis; Programmed Necrosis; Immune-response; Deficiency; Disease; Complex; Iaps
ISSN (print) / ISBN 2211-1247
e-ISSN 2211-1247
Zeitschrift Cell Reports
Quellenangaben Band: 7, Heft: 6, Seiten: 1796-1808 Artikelnummer: , Supplement: ,
Verlag Cell Press
Verlagsort Cambridge
Begutachtungsstatus Peer reviewed