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

Lawlor, KE; Feltham, R; Yabal, M; Conos, SA; Chen, KW; Ziehe, S; Grass, C; Zhan, Y; Nguyen, TA; Hall, C; Vince, AJ; Chatfield, SM; D&#39;Silva, DB; Pang, KC; Schroder, K; Silke, J; Vaux, DL; Jost, PJ; Vince, JE

Author(s): Lawlor, KE; Feltham, R; Yabal, M; Conos, SA; Chen, KW; Ziehe, S; Grass, C; Zhan, Y; Nguyen, TA; Hall, C; Vince, AJ; Chatfield, SM; D'Silva, DB; Pang, KC; Schroder, K; Silke, J; Vaux, DL; Jost, PJ; Vince, JE;
Details: Publication Year 2017-07-18,Volume 20,Issue #3,Page 668-682
Journal Title: Cell Reports
Publication Type: Journal Article
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-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.
Publisher: Elsevier
Research Division(s): Inflammation; Immunology; Cell Signalling And Cell Death
PubMed ID: 28723569
Publisher's Version: https://doi.org/10.1016/j.celrep.2017.06.073
Open Access at Publisher's Site: http://www.sciencedirect.com.science/article/pii/S221112471730904X?via%3Dihub
NHMRC Grants: NHMRC/1052598, NHMRC/1051210, NHMRC/1101405, NHMRC/1064591, NHMRC/1081272, NHMRC/461221,
Terms of Use/Rights Notice: https://creativecommons.org/licenses/by-nc-nd/4.0/
Documents: Lawlor et al Cell Reports_2017.pdf - (4.68MB, application/pdf)

Creation Date: 2017-08-30 02:22:40

Last Modified: 2017-09-04 03:37:59