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XIAP restricts TNF- and RIP3-dependent cell death and inflammasome activation

Monica Yabal1, Nicole Müller1, Heiko Adler2

  • 1III. Medizinische Klink, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.

Cell Reports
|June 3, 2014
PubMed

Insights

X-linked inhibitor of apoptosis protein (XIAP) loss causes excessive cell death and IL-1β release. This links XIAP"s role in regulating immune responses to X-linked lymphoproliferative syndrome type 2 (XLP-2) and hyperinflammation.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Medicine

Background:

  • X-linked inhibitor of apoptosis protein (XIAP) is crucial for regulating innate immune responses.
  • Loss-of-function mutations in XIAP lead to X-linked lymphoproliferative syndrome type 2 (XLP-2) in humans.

Purpose of the Study:

  • To investigate the role of XIAP in regulating cell death and IL-1β secretion in response to immune stimuli.
  • To elucidate the molecular mechanisms underlying XIAP-mediated immune regulation and its connection to XLP-2.

Main Methods:

  • Utilized gene-targeted mice lacking XIAP or its RING domain.
  • Stimulated dendritic cells with Toll-like receptor agonists.
  • Analyzed cell death, IL-1β secretion, and ubiquitylation of key signaling proteins (RIP1, RIP3).
  • Observed disease phenotypes in virally infected Xiap(-/-) mice.

Main Results:

  • Loss of XIAP resulted in excessive dendritic cell death and IL-1β secretion upon Toll-like receptor stimulation.
  • Aberrant IL-1β secretion and cell death were dependent on TNF and RIP3, but independent of cIAP1/cIAP2 and caspases.
  • XIAP deficiency led to increased RIP1 ubiquitylation outside of TNFR complex I.
  • Xiap(-/-) mice exhibited symptoms similar to XLP-2 when infected with viruses.

Conclusions:

  • XIAP is essential for controlling RIP3-dependent cell death and IL-1β secretion induced by TNF.
  • Dysregulation of XIAP function contributes to hyperinflammation observed in XLP-2 patients.

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