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.
authors.affiliation: III. Medizinische Klink, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
authors.forename: Monica
authors.initials: M
authors.lastname: Yabal
authors.affiliation: III. Medizinische Klink, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Müller
authors.affiliation: Research Unit Gene Vectors, Helmholtz Zentrum München-German Research Center for Environmental Health, GmbH, 85764 Oberschleissheim, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Adler
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Knies
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Groß
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Rune Busk
authors.initials: RB
authors.lastname: Damgaard
authors.affiliation: Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kanegane
authors.affiliation: Institute of Virology, Technische Universität München and Helmholtz Zentrum München, 81675 München, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Ringelhan
authors.affiliation: Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kaufmann
authors.affiliation: Institute of Virology, Technische Universität München and Helmholtz Zentrum München, 81675 München, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwälder
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville,VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Groß
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ruland
authors.affiliation: III. Medizinische Klink, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Peschel
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Gyrd-Hansen
authors.affiliation: III. Medizinische Klink, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany. Electronic address: philipp.jost@lrz.tum.de.
authors.forename: Philipp J
authors.initials: PJ
authors.lastname: Jost
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D005260:Female; D058847:Inflammasomes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse