XIAP Restricts TNF- and RIP3-Dependent Cell Death and Inflammasome Activation
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XIAP Restricts TNF- and RIP3-Dependent Cell Death and Inflammasome Activation. / Yabal, Monica; Müller, Nicole; Adler, Heiko; Knies, Nathalie; Groß, Christina J; Damgaard, Rune Busk; Kanegane, Hirokazu; Ringelhan, Marc; Kaufmann, Thomas; Heikenwälder, Mathias; Strasser, Andreas; Groß, Olaf; Ruland, Jürgen; Peschel, Christian; Gyrd-Hansen, Mads; Jost, Philipp J.
In: Cell Reports, Vol. 7, No. 6, 26.06.2014, p. 1796-1808.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - XIAP Restricts TNF- and RIP3-Dependent Cell Death and Inflammasome Activation
AU - Yabal, Monica
AU - Müller, Nicole
AU - Adler, Heiko
AU - Knies, Nathalie
AU - Groß, Christina J
AU - Damgaard, Rune Busk
AU - Kanegane, Hirokazu
AU - Ringelhan, Marc
AU - Kaufmann, Thomas
AU - Heikenwälder, Mathias
AU - Strasser, Andreas
AU - Groß, Olaf
AU - Ruland, Jürgen
AU - Peschel, Christian
AU - Gyrd-Hansen, Mads
AU - Jost, Philipp J
N1 - Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2014/6/26
Y1 - 2014/6/26
N2 - 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.
AB - 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.
U2 - 10.1016/j.celrep.2014.05.008
DO - 10.1016/j.celrep.2014.05.008
M3 - Journal article
C2 - 24882010
VL - 7
SP - 1796
EP - 1808
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 6
ER -
ID: 117867943