Caspase-8-driven apoptotic and pyroptotic crosstalk causes cell death and IL-1β release in X-linked inhibitor of apoptosis (XIAP) deficiency

Hughes, SA; Lin, M; Weir, A; Huang, B; Xiong, L; Chua, NK; Pang, J; Santavanond, JP; Tixeira, R; Doerflinger, M; Deng, Y; Yu, CH; Silke, N; Conos, SA; Frank, D; Simpson, DS; Murphy, JM; Lawlor, KE; Pearson, JS; Silke, J; Pellegrini, M; Herold, MJ; Poon, IKH; Masters, SL; Li, M; Tang, Q; Zhang, Y; Rashidi, M; Geng, L; Vince, JE

Author(s): Hughes, SA; Lin, M; Weir, A; Huang, B; Xiong, L; Chua, NK; Pang, J; Santavanond, JP; Tixeira, R; Doerflinger, M; Deng, Y; Yu, CH; Silke, N; Conos, SA; Frank, D; Simpson, DS; Murphy, JM; Lawlor, KE; Pearson, JS; Silke, J; Pellegrini, M; Herold, MJ; Poon, IKH; Masters, SL; Li, M; Tang, Q; Zhang, Y; Rashidi, M; Geng, L; Vince, JE;
Details: Publication Year 2023-03-01,Volume 42,Issue #5,Page e110468
Journal Title: EMBO Journal
Abstract: Genetic lesions in X-linked inhibitor of apoptosis (XIAP) pre-dispose humans to cell death-associated inflammatory diseases, although the underlying mechanisms remain unclear. Here, we report that two patients with XIAP deficiency-associated inflammatory bowel disease display increased inflammatory IL-1β maturation as well as cell death-associated caspase-8 and Gasdermin D (GSDMD) processing in diseased tissue, which is reduced upon patient treatment. Loss of XIAP leads to caspase-8-driven cell death and bioactive IL-1β release that is only abrogated by combined deletion of the apoptotic and pyroptotic cell death machinery. Namely, extrinsic apoptotic caspase-8 promotes pyroptotic GSDMD processing that kills macrophages lacking both inflammasome and apoptosis signalling components (caspase-1, -3, -7, -11 and BID), while caspase-8 can still cause cell death in the absence of both GSDMD and GSDME when caspase-3 and caspase-7 are present. Neither caspase-3 and caspase-7-mediated activation of the pannexin-1 channel, or GSDMD loss, prevented NLRP3 inflammasome assembly and consequent caspase-1 and IL-1β maturation downstream of XIAP inhibition and caspase-8 activation, even though the pannexin-1 channel was required for NLRP3 triggering upon mitochondrial apoptosis. These findings uncouple the mechanisms of cell death and NLRP3 activation resulting from extrinsic and intrinsic apoptosis signalling, reveal how XIAP loss can co-opt dual cell death programs, and uncover strategies for targeting the cell death and inflammatory pathways that result from XIAP deficiency.
Publisher: EMBO Press/Wiley
Keywords: Humans; Apoptosis; Caspase 1/genetics/metabolism; Caspase 3/metabolism; Caspase 7/metabolism; Caspase 8/genetics/metabolism; Cell Death; *Inflammasomes/metabolism; Interleukin-1beta/genetics/metabolism; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism; Pyroptosis/physiology; X-Linked Inhibitor of Apoptosis Protein/genetics/metabolism; Gasdermin D; Xiap; caspase-8; inflammasome; pyroptosis
Research Division(s): Inflammation; Blood Cells And Blood Cancer; Infectious Diseases And Immune Defence; Ubiquitin Signalling
PubMed ID: 36647737
Publisher's Version: https://doi.org/10.15252/embj.2021110468
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-03-08 03:15:56

Last Modified: 2023-03-08 03:57:05