Poster Presentation Lorne Infection and Immunity 2019

Mechanistic insights into hyperinflammation caused by XIAP deficiency (#150)

Kate Lawlor 1 2 3 4 , Rebecca Feltham 3 4 , Monica Yabal 5 , Stephanie Conos 3 4 , Kaiwen Chen 6 , Kate Schroder 6 , John Silke 3 4 , David Vaux 3 4 , Philipp Jost 5 , James Vince 3 4
  1. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia
  2. Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia
  3. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
  4. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  5. III. Medical Deapertment for Hematology and Oncology, Kliniklum rechts der lsar, Technische Universität München, München, Germany
  6. Institute for Molecular Bioscience and Centre for Inflammation and Disease Research, The University of Queensland, St Lucia, QLD, Australia

X-linked Inhibitor of Apoptosis (XIAP) deficiency predispose people to pathogen-associated hyperinflammation. Upon XIAP loss, Toll-like receptor (TLR) ligation triggers RIPK3-caspase-8-mediated IL-1β activation and cell death in myeloid cells. How XIAP suppresses these events is unclear. We now show that TLR-MyD88 signalling causes the proteasomal degradation of the related IAP, cIAP1, and its adaptor, TRAF2, by inducing TNF and TNF Receptor 2 (TNFR2) signalling. Genetically, we define that cIAP1 loss is required to promote RIPK3-caspase-8-mediated inflammatory events in the absence of XIAP. Importantly, loss of TNFR2 in XIAP-deficient macrophages limits TLR-MyD88-induced cIAP1 degradation, cell death and IL-1β activation. These data reveal that a TLR-MyD88-TNF-TNFR2 axis drives cIAP1-TRAF degradation to allow TLR or TNFR1 signalling to activate RIPK3-caspase-8 and IL-1β upon XIAP loss. This mechanism may explain why XIAP-deficient patients can exhibit symptoms reminiscent of patients with activating inflammasome mutations.