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

Cell Rep. 2014 Jun 26;7(6):1796-808. doi: 10.1016/j.celrep.2014.05.008. Epub 2014 May 29.

Authors

Monica Yabal¹, Nicole Müller¹, Heiko Adler², Nathalie Knies³, Christina J Groß³, Rune Busk Damgaard⁴, Hirokazu Kanegane⁵, Marc Ringelhan⁶, Thomas Kaufmann⁷, Mathias Heikenwälder⁶, Andreas Strasser⁸, Olaf Groß³, Jürgen Ruland³, Christian Peschel¹, Mads Gyrd-Hansen⁴, Philipp J Jost⁹

Affiliations

¹ III. Medizinische Klink, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
² Research Unit Gene Vectors, Helmholtz Zentrum München-German Research Center for Environmental Health, GmbH, 85764 Oberschleissheim, Germany.
³ Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
⁴ Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
⁵ Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
⁶ Institute of Virology, Technische Universität München and Helmholtz Zentrum München, 81675 München, Germany.
⁷ Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland.
⁸ The Walter and Eliza Hall Institute of Medical Research, Parkville,VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
⁹ III. Medizinische Klink, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany. Electronic address: philipp.jost@lrz.tum.de.

PMID: 24882010
DOI: 10.1016/j.celrep.2014.05.008

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / physiology
Cell Death / physiology
Dendritic Cells / cytology
Dendritic Cells / drug effects
Dendritic Cells / physiology*
Female
Inflammasomes / drug effects
Inflammasomes / genetics
Inflammasomes / metabolism
Inflammasomes / physiology*
Interleukin-1beta / genetics
Interleukin-1beta / metabolism
Interleukin-1beta / physiology
Lipopolysaccharides / pharmacology
Male
Mice
Mice, Transgenic
Receptor-Interacting Protein Serine-Threonine Kinases / genetics
Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
Receptor-Interacting Protein Serine-Threonine Kinases / physiology*
Tumor Necrosis Factor-alpha / genetics
Tumor Necrosis Factor-alpha / metabolism
Tumor Necrosis Factor-alpha / physiology*
X-Linked Inhibitor of Apoptosis Protein / genetics
X-Linked Inhibitor of Apoptosis Protein / metabolism
X-Linked Inhibitor of Apoptosis Protein / physiology*

Substances

Inflammasomes
Interleukin-1beta
Lipopolysaccharides
Tumor Necrosis Factor-alpha
X-Linked Inhibitor of Apoptosis Protein
Receptor-Interacting Protein Serine-Threonine Kinases
Ripk3 protein, mouse