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

Research output: Contribution to journalJournal articleResearchpeer-review

  • 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

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 languageEnglish
JournalCell Reports
Issue number6
Pages (from-to)1796-1808
Publication statusPublished - 26 Jun 2014

ID: 117867943