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

Author

Kate E. Lawlor, Rebecca Feltham, Monica Yabal, Stephanie A. Conos, Kaiwen W. Chen, Stephanie Ziehe, Carina Graß, Yifan Zhan, Tan A. Nguyen, Cathrine Hall, Angelina J. Vince, Simon M. Chatfield, Damian B. D’Silva, Kenneth C. Pang, Kate Schroder, John Silke, David L. Vaux, Philipp J. Jost, and James E. Vince

Subjects
Toll-like receptor, NLRP3, RIPK3, caspase-8, TNFR2, XIAP, cIAP1, necroptosis, interferon, autoinflammatory disease, Biology (General), QH301-705.5
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.

Published
2017
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2. XIAP Loss Triggers RIPK3- and Caspase-8-Driven IL-1β Activation and Cell Death as a Consequence of TLR-MyD88-Induced cIAP1-TRAF2 Degradation

Author

Philipp J. Jost, Angelina J. Vince, Stephanie A. Conos, Yifan Zhan, Kate Schroder, David L. Vaux, Simon M Chatfield, Monica Yabal, Carina Graß, Stephanie Ziehe, John Silke, Kaiwen W. Chen, Kate E. Lawlor, Ken C Pang, Tan A. Nguyen, James E Vince, Damian B D'Silva, Rebecca Feltham, Cathrine Hall, Lawlor, Kate E, Feltham, Rebecca, Yabal, Monica, Conos, Stephanie A, Chen, Kaiwen W, Ziehe, Stephanie, Graß, Carina, Zhan, Yifan, Nguyen, Tan A, Hall, Cathrine, Vince, Angelina J, Chatfield, Simon M, D'Silva, Damian B, Pang, Kenneth C, Schroder, Kate, Silke, John, Vaux, David L, Jost, Philipp J, and Vince, James E

Subjects
0301 basic medicine, Programmed cell death, TRAF2, proteasomal degradation, Necroptosis, Interleukin-1beta, necroptosis, Inhibitor of apoptosis, Caspase 8, RIPK3, General Biochemistry, Genetics and Molecular Biology, caspase-8, Inhibitor of Apoptosis Proteins, 03 medical and health sciences, Mice, XIAP, NLRP3, autoinflammatory disease, autoinflammatory conditions, Toll-like receptor, medicine, XIAP deficiency, Animals, XIAP Deficiency, lcsh:QH301-705.5, Mice, Knockout, Cell Death, Chemistry, Toll-Like Receptors, apoptosis, Inflammasome, interferon, TNF Receptor-Associated Factor 2, 3. Good health, cIAP1, TNFR2, 030104 developmental biology, cell death, interleukin (IL)-18, lcsh:Biology (General), Receptor-Interacting Protein Serine-Threonine Kinases, Myeloid Differentiation Factor 88, Proteolysis, Cancer research, medicine.drug
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. Refereed/Peer-reviewed

Published
2017

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