Journal article
Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner
SA Conos, KW Chen, D De Nardo, H Hara, L Whitehead, G Núñez, SL Masters, JM Murphy, K Schroder, DL Vaux, KE Lawlor, LM Lindqvist, JE Vince
Proceedings of the National Academy of Sciences of the United States of America | NATL ACAD SCIENCES | Published : 2017
Abstract
Necroptosis is a physiological cell suicide mechanism initiated by receptor-interacting protein kinase-3 (RIPK3) phosphorylation of mixed-lineage kinase domain-like protein (MLKL), which results in disruption of the plasma membrane. Necroptotic cell lysis, and resultant release of proinflammatory mediators, is thought to cause inflammation in necroptotic disease models. However, we previously showed that MLKL signaling can also promote inflammation by activating the nucleotide-binding oligomerization domain (NOD)- like receptor protein 3 (NLRP3) inflammasome to recruit the adaptor protein apoptosis-Associated speck-like protein containing a caspase activation and recruitment domain (ASC) and..
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Awarded by State Government of Victoria
Funding Acknowledgements
We thank S. Young (WEHI) for MLKL lentiviral plasmids, M. Rashidi (WEHI) for NF-kappa B THP1 reporter cells and human ELISA kits, J. Silke and W. Alexander (WEHI) for mice, A. Stock for the Ly5.2 antibody, J. Hildebrand and M. Tanzer (WEHI) for assistance with the Blue Native PAGE, Paul Baker (WEHI) for assistance with the LDH assay, R. Crawley for animal care, and S. Monard and staff for cell sorting. This work was supported by NIH Grants R01AI063331 and R01DK091191 (to G.N.); Australian National Health and Medical Research Council Project Grants 1051210, 1101405, and 1057905; Fellowships 1052598 (to J.E.V.), 1035502 (to L.M.L.), 1020136 (to D.L.V.), and 1105754 (to J. M. M.); and Program Grant 461221; Australian Research Council Project Grant DP160102702 and Fellowship FT130100361 (to K.S.); and operational infrastructure grants through the Australian Government Independent Research Institute Infrastructure Support Scheme (9000220) and the Victorian State Government Operational Infrastructure Support Program.