Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Lawlor, KE; Feltham, R; Yabal, M; Conos, SA; Chen, KW; Ziehe, S; Graß, C; Zhan, Y; Nguyen, TA; Hall, C; Vince, AJ; Chatfield, SM; D'Silva, DB; Pang, KC; Schroder, K; Silke, J; Vaux, DL; Jost, PJ; Vince, JE.
XIAP Loss Triggers RIPK3- and Caspase-8-Driven IL-1β Activation and Cell Death as a Consequence of TLR-MyD88-Induced cIAP1-TRAF2 Degradation.
Cell Rep. 2017; 20(3):668-682
Doi: 10.1016/j.celrep.2017.06.073
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- Co-Autor*innen der Med Uni Graz
- Jost Philipp
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- Abstract:
- X-linked Inhibitor of Apoptosis (XIAP) deficiency predisposes people to pathogen-associated hyperinflammation. Upon XIAP loss, Toll-like receptor (TLR) ligation triggers RIPK3-caspase-8-mediated IL-1β activation and death in myeloid cells. How XIAP suppresses these events remains unclear. Here, we show that TLR-MyD88 causes the proteasomal degradation of the related IAP, cIAP1, and its adaptor, TRAF2, by inducing TNF and TNF Receptor 2 (TNFR2) signaling. Genetically, we define that myeloid-specific cIAP1 loss promotes TLR-induced RIPK3-caspase-8 and IL-1β activity in the absence of XIAP. Importantly, deletion of TNFR2 in XIAP-deficient cells limited TLR-MyD88-induced cIAP1-TRAF2 degradation, cell death, and IL-1β activation. In contrast to TLR-MyD88, TLR-TRIF-induced interferon (IFN)β inhibited cIAP1 loss and consequent cell death. These data reveal how, upon XIAP deficiency, a TLR-TNF-TNFR2 axis drives cIAP1-TRAF2 degradation to allow TLR or TNFR1 activation of RIPK3-caspase-8 and IL-1β. This mechanism may explain why XIAP-deficient patients can exhibit symptoms reminiscent of patients with activating inflammasome mutations. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Caspase 8 - genetics
- Caspase 8 - metabolism
- Cell Death -
- Inhibitor of Apoptosis Proteins - deficiency
- Inhibitor of Apoptosis Proteins - genetics
- Inhibitor of Apoptosis Proteins - metabolism
- Interleukin-1beta - genetics
- Interleukin-1beta - metabolism
- Mice -
- Mice, Knockout -
- Myeloid Differentiation Factor 88 - genetics
- Myeloid Differentiation Factor 88 - metabolism
- Proteolysis -
- Receptor-Interacting Protein Serine-Threonine Kinases - genetics
- Receptor-Interacting Protein Serine-Threonine Kinases - metabolism
- TNF Receptor-Associated Factor 2 - genetics
- TNF Receptor-Associated Factor 2 - metabolism
- Toll-Like Receptors - genetics
- Toll-Like Receptors - metabolism