| First Author | Lawlor KE | Year | 2017 |
| Journal | Cell Rep | Volume | 20 |
| Issue | 3 | Pages | 668-682 |
| PubMed ID | 28723569 | Mgi Jnum | J:254238 |
| Mgi Id | MGI:6104225 | Doi | 10.1016/j.celrep.2017.06.073 |
| Citation | Lawlor KE, et al. (2017) XIAP Loss Triggers RIPK3- and Caspase-8-Driven IL-1beta Activation and Cell Death as a Consequence of TLR-MyD88-Induced cIAP1-TRAF2 Degradation. Cell Rep 20(3):668-682 |
| abstractText | 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-1beta 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-1beta 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-1beta activation. In contrast to TLR-MyD88, TLR-TRIF-induced interferon (IFN)beta 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-1beta. This mechanism may explain why XIAP-deficient patients can exhibit symptoms reminiscent of patients with activating inflammasome mutations. |
