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XIAP loss triggers RIPK3-and Caspase-8-driven IL-1β activation and cell death as a consequence of TLR-MyD88-induced cIAP1-TRAF2 degradation

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dc.contributor.authorLawlor, K.E.
dc.contributor.authorFeltham, R.
dc.contributor.authorYabal, M.
dc.contributor.authorConos, S.A.
dc.contributor.authorChen, K.W.
dc.contributor.authorZiehe, S.
dc.contributor.authorGraß, C.
dc.contributor.authorZhan, Y.
dc.contributor.authorNguyen, T.A.
dc.contributor.authorHall, C.
dc.contributor.authorVince, A.J.
dc.contributor.authorChatfield, S.M.
dc.contributor.authorD'Silva, D.B.
dc.contributor.authorPang, K.C.
dc.contributor.authorSchroder, K.
dc.contributor.authorSilke, J.
dc.contributor.authorVaux, D.L.
dc.contributor.authorJost, P.J.
dc.contributor.authorVince, J.E.
dc.date.issued2017
dc.descriptionData source: Supplementary information, https://doi.org/10.1016/j.celrep.2017.06.073
dc.description.abstractX-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.
dc.identifier.citationCell reports, 2017; 20(3):668-682
dc.identifier.doi10.1016/j.celrep.2017.06.073
dc.identifier.issn2211-1247
dc.identifier.urihttps://hdl.handle.net/11541.2/131574
dc.language.isoen
dc.publisherElsevier
dc.relation.fundingNHMRC 1051210
dc.relation.fundingNHMRC 1101405
dc.relation.fundingNHMRC 1064591
dc.relation.fundingNHMRC 1081272
dc.relation.fundingVictorian State Government
dc.relation.fundingDeutsche Jose Carreras Leukamie Stiftung R 12/22
dc.relation.fundingDFG FOR2036
dc.rightsCopyright 2017 The Author(s).This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). (http://creativecommons.org/licenses/by-nc-nd/4.0/)
dc.source.urihttps://doi.org/10.1016/j.celrep.2017.06.073
dc.subjectapoptosis
dc.subjectproteasomal degradation
dc.subjectcell death
dc.subjectXIAP deficiency
dc.subjectinterleukin (IL)-18
dc.subjectautoinflammatory conditions
dc.titleXIAP loss triggers RIPK3-and Caspase-8-driven IL-1β activation and cell death as a consequence of TLR-MyD88-induced cIAP1-TRAF2 degradation
dc.typeJournal article
pubs.publication-statusPublished
ror.mmsid9916187608801831

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