XIAP Loss Triggers RIPK3- and Caspase-8-Driven IL-1β Activation and Cell Death as a Consequence of TLR-MyD88-Induced cIAP1-TRAF2 Degradation.

Details

Serval ID
serval:BIB_BE672E83ECEB
Type
Article: article from journal or magazin.
Collection
Publications
Title
XIAP Loss Triggers RIPK3- and Caspase-8-Driven IL-1β Activation and Cell Death as a Consequence of TLR-MyD88-Induced cIAP1-TRAF2 Degradation.
Journal
Cell reports
Author(s)
Lawlor K.E., Feltham R., Yabal M., Conos S.A., Chen K.W., Ziehe S., Graß C., Zhan Y., Nguyen T.A., Hall C., Vince A.J., Chatfield S.M., D'Silva D.B., Pang K.C., Schroder K., Silke J., Vaux D.L., Jost P.J., Vince J.E.
ISSN
2211-1247 (Electronic)
Publication state
Published
Issued date
18/07/2017
Peer-reviewed
Oui
Volume
20
Number
3
Pages
668-682
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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.
Keywords
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, NLRP3, RIPK3, TNFR2, Toll-like receptor, XIAP, autoinflammatory disease, cIAP1, caspase-8, interferon, necroptosis
Pubmed
Web of science
Open Access
Yes
Create date
22/09/2018 20:01
Last modification date
21/08/2019 5:35
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