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

doi:10.1016/j.celrep.2017.06.073

. 2017 Jul 18;20(3):668-682.

doi: 10.1016/j.celrep.2017.06.073.

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

Kate E Lawlor¹, Rebecca Feltham², Monica Yabal³, Stephanie A Conos², Kaiwen W Chen⁴, Stephanie Ziehe³, Carina Graß³, Yifan Zhan², Tan A Nguyen², Cathrine Hall⁵, Angelina J Vince⁵, Simon M Chatfield², Damian B D'Silva⁵, Kenneth C Pang⁶, Kate Schroder⁴, John Silke², David L Vaux², Philipp J Jost³, James E Vince⁷

Affiliations

¹ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: lawlor@wehi.edu.au.
² The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
³ III. Medical Department for Hematology and Oncology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
⁴ Institute for Molecular Bioscience and Centre for Inflammation and Disease Research, The University of Queensland, St. Lucia, QLD 4072, Australia.
⁵ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
⁶ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC 3010, Australia; Department of Psychiatry, University of Melbourne, Parkville, VIC 3010, Australia; Murdoch Childrens Research Institute, Parkville, VIC 3052, Australia.
⁷ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: vince@wehi.edu.au.

PMID: 28723569
DOI: 10.1016/j.celrep.2017.06.073

Free article

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

Kate E Lawlor et al. Cell Rep. 2017.

Free article

. 2017 Jul 18;20(3):668-682.

doi: 10.1016/j.celrep.2017.06.073.

Authors

Affiliations

¹ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: lawlor@wehi.edu.au.
² The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
³ III. Medical Department for Hematology and Oncology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
⁴ Institute for Molecular Bioscience and Centre for Inflammation and Disease Research, The University of Queensland, St. Lucia, QLD 4072, Australia.
⁵ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
⁶ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC 3010, Australia; Department of Psychiatry, University of Melbourne, Parkville, VIC 3010, Australia; Murdoch Childrens Research Institute, Parkville, VIC 3052, Australia.
⁷ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: vince@wehi.edu.au.

PMID: 28723569
DOI: 10.1016/j.celrep.2017.06.073

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: NLRP3; RIPK3; TNFR2; Toll-like receptor; XIAP; autoinflammatory disease; cIAP1; caspase-8; interferon; necroptosis.

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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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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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