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

Monica Yabal; Nicole Müller; Heiko Adler; Nathalie Knies; Christina J Groß; Rune Busk Damgaard; Hirokazu Kanegane; Marc Ringelhan; Thomas Kaufmann; Mathias Heikenwälder; Andreas Strasser; Olaf Groß; Jürgen Ruland; Christian Peschel; Mads Gyrd-Hansen; Philipp J Jost

doi:10.1016/j.celrep.2014.05.008

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

Monica Yabal, Nicole Müller, Heiko Adler, Nathalie Knies, Christina J Groß, Rune Busk Damgaard, Hirokazu Kanegane, Marc Ringelhan, Thomas Kaufmann, Mathias Heikenwälder, Andreas Strasser, Olaf Groß, Jürgen Ruland, Christian Peschel, Mads Gyrd-Hansen, Philipp J Jost

Novo Nordisk Foundation Center for Protein Research

147 Citations (Scopus)

Abstract

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 language	English
Journal	Cell Reports
Volume	7
Issue number	6
Pages (from-to)	1796-1808
ISSN	2211-1247
DOIs	https://doi.org/10.1016/j.celrep.2014.05.008
Publication status	Published - 26 Jun 2014

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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. (2014). XIAP Restricts TNF- and RIP3-Dependent Cell Death and Inflammasome Activation. Cell Reports, 7(6), 1796-1808. https://doi.org/10.1016/j.celrep.2014.05.008

Yabal, M, Müller, N, Adler, H, Knies, N, Groß, CJ, Damgaard, RB, Kanegane, H, Ringelhan, M, Kaufmann, T, Heikenwälder, M, Strasser, A, Groß, O, Ruland, J, Peschel, C, Gyrd-Hansen, M & Jost, PJ 2014, 'XIAP Restricts TNF- and RIP3-Dependent Cell Death and Inflammasome Activation', Cell Reports, vol. 7, no. 6, pp. 1796-1808. https://doi.org/10.1016/j.celrep.2014.05.008

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title = "XIAP Restricts TNF- and RIP3-Dependent Cell Death and Inflammasome Activation",

abstract = "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.",

author = "Monica Yabal and Nicole M{\"u}ller and Heiko Adler and Nathalie Knies and Gro{\ss}, {Christina J} and Damgaard, {Rune Busk} and Hirokazu Kanegane and Marc Ringelhan and Thomas Kaufmann and Mathias Heikenw{\"a}lder and Andreas Strasser and Olaf Gro{\ss} and J{\"u}rgen Ruland and Christian Peschel and Mads Gyrd-Hansen and Jost, {Philipp J}",

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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

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

SN - 2639-1856

VL - 7

SP - 1796

EP - 1808

JO - Cell Reports

JF - Cell Reports

IS - 6

ER -

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

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