Journal article
RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL
KE Lawlor, N Khan, A Mildenhall, M Gerlic, BA Croker, AA D'Cruz, C Hall, S Kaur Spall, H Anderton, SL Masters, M Rashidi, IP Wicks, WS Alexander, Y Mitsuuchi, CA Benetatos, SM Condon, WWL Wong, J Silke, DL Vaux, JE Vince
Nature Communications | Published : 2015
DOI: 10.1038/ncomms7282
Abstract
RIPK3 and its substrate MLKL are essential for necroptosis, a lytic cell death proposed to cause inflammation via the release of intracellular molecules. Whether and how RIPK3 might drive inflammation in a manner independent of MLKL and cell lysis remains unclear. Here we show that following LPS treatment, or LPS-induced necroptosis, the TLR adaptor protein TRIF and inhibitor of apoptosis proteins (IAPs: X-linked IAP, cellular IAP1 and IAP2) regulate RIPK3 and MLKL ubiquitylation. Hence, when IAPs are absent, LPS triggers RIPK3 to activate caspase-8, promoting apoptosis and NLRP3-caspase-1 activation, independent of RIPK3 kinase activity and MLKL. In contrast, in the absence of both IAPs and..
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Awarded by State Government of Victoria
Funding Acknowledgements
We thank Vishva Dixit for Ripk<SUP>3-/-</SUP> mice, Michelle Kelliher for Ripk1<SUP>-/-</SUP> mice, Heinrich Korner for Tnf<SUP>-/-</SUP> and Stephen Hedrick for Casp8<SUP>fl/fl</SUP> mice; Lisa Lindqvist and Thomas Naderer for critically reading the manuscript and James Murphy for scientific discussions; E. Tsui for preparation of histology; N. Lynch, K. Trueman, L. Kyran, K. Vella, L. Scott, C. Yates for animal care; S. Monard and staff for cell sorting; J. Corbin for Advia cell counts; K. Rogers, J. O'Donnell and K. McArthur for assistance with imaging; Thomas Haimowitz and Yijun Deng for IAP antagonist synthesis and structural information. This work was supported by National Health and Medical Research (Canberra, Australia) Project grants (1051210, 1025594, 1057905), fellowships (J.E.V. (1052598), I.P.W. (1023407), J.S. (541901)) and Program Grants (1016647 and 461221) and operational infrastructure grants through the Australian Government IRISS and the Victorian State Government OIS. W.W-L.W. was supported by a SNF grant (310030138085) and I.P.W. by the Reid Charitable Trusts.