RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL

Kate E. Lawlor; Nufail Khan; Alison Mildenhall; Motti Gerlic; Ben A. Croker; Akshay A. D'Cruz; Cathrine Hall; Sukhdeep Kaur Spall; Holly Anderton; Seth L. Masters; Maryam Rashidi; Ian P. Wicks; Warren S. Alexander; Yasuhiro Mitsuuchi; Christopher A. Benetatos; Stephen M. Condon; W. Wei Lynn Wong; John Silke; David L. Vaux; James E. Vince

doi:10.1038/ncomms7282

RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL

Kate E. Lawlor, Nufail Khan, Alison Mildenhall, Motti Gerlic, Ben A. Croker, Akshay A. D'Cruz, Cathrine Hall, Sukhdeep Kaur Spall, Holly Anderton, Seth L. Masters, Maryam Rashidi, Ian P. Wicks, Warren S. Alexander, Yasuhiro Mitsuuchi, Christopher A. Benetatos, Stephen M. Condon, W. Wei Lynn Wong, John Silke, David L. Vaux, James E. Vince^*

^*Corresponding author for this work

Clinical Microbiology and Immunology

Research output: Contribution to journal › Article › peer-review

538 Scopus citations

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 caspase-8, RIPK3 kinase activity and MLKL are essential for TLR-induced NLRP3 activation. Consistent with in vitro experiments, interleukin-1 (IL-1)-dependent autoantibody-mediated arthritis is exacerbated in mice lacking IAPs, and is reduced by deletion of RIPK3, but not MLKL. Therefore RIPK3 can promote NLRP3 inflammasome and IL-1 β inflammatory responses independent of MLKL and necroptotic cell death.

Original language	English
Article number	6282
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7282
State	Published - 18 Feb 2015

Funding

Funders	Funder number
Reid Charitable Trusts
State Government of Victoria
National Health and Medical Research	1016647, 1057905, 461221, 1051210
National Health and Medical Research Council	1052598, 541901, 1025594
National Science Foundation	1023407
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	310030-138085

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ncomms7282

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Lawlor, K. E., Khan, N., Mildenhall, A., Gerlic, M., Croker, B. A., D'Cruz, A. A., Hall, C., Kaur Spall, S., Anderton, H., Masters, S. L., Rashidi, M., Wicks, I. P., Alexander, W. S., Mitsuuchi, Y., Benetatos, C. A., Condon, S. M., Wong, W. W. L., Silke, J., Vaux, D. L., & Vince, J. E. (2015). RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL. Nature Communications, 6, Article 6282. https://doi.org/10.1038/ncomms7282

@article{5a616d17d0ad498a96cbed98f10dfe97,

title = "RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL",

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 caspase-8, RIPK3 kinase activity and MLKL are essential for TLR-induced NLRP3 activation. Consistent with in vitro experiments, interleukin-1 (IL-1)-dependent autoantibody-mediated arthritis is exacerbated in mice lacking IAPs, and is reduced by deletion of RIPK3, but not MLKL. Therefore RIPK3 can promote NLRP3 inflammasome and IL-1 β inflammatory responses independent of MLKL and necroptotic cell death.",

author = "Lawlor, {Kate E.} and Nufail Khan and Alison Mildenhall and Motti Gerlic and Croker, {Ben A.} and D'Cruz, {Akshay A.} and Cathrine Hall and {Kaur Spall}, Sukhdeep and Holly Anderton and Masters, {Seth L.} and Maryam Rashidi and Wicks, {Ian P.} and Alexander, {Warren S.} and Yasuhiro Mitsuuchi and Benetatos, {Christopher A.} and Condon, {Stephen M.} and Wong, {W. Wei Lynn} and John Silke and Vaux, {David L.} and Vince, {James E.}",

note = "Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited.",

year = "2015",

month = feb,

day = "18",

doi = "10.1038/ncomms7282",

language = "אנגלית",

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Lawlor, KE, Khan, N, Mildenhall, A, Gerlic, M, Croker, BA, D'Cruz, AA, Hall, C, Kaur Spall, S, Anderton, H, Masters, SL, Rashidi, M, Wicks, IP, Alexander, WS, Mitsuuchi, Y, Benetatos, CA, Condon, SM, Wong, WWL, Silke, J, Vaux, DL & Vince, JE 2015, 'RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL', Nature Communications, vol. 6, 6282. https://doi.org/10.1038/ncomms7282

TY - JOUR

T1 - RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL

AU - Lawlor, Kate E.

AU - Khan, Nufail

AU - Mildenhall, Alison

AU - Gerlic, Motti

AU - Croker, Ben A.

AU - D'Cruz, Akshay A.

AU - Hall, Cathrine

AU - Kaur Spall, Sukhdeep

AU - Anderton, Holly

AU - Masters, Seth L.

AU - Rashidi, Maryam

AU - Wicks, Ian P.

AU - Alexander, Warren S.

AU - Mitsuuchi, Yasuhiro

AU - Benetatos, Christopher A.

AU - Condon, Stephen M.

AU - Wong, W. Wei Lynn

AU - Silke, John

AU - Vaux, David L.

AU - Vince, James E.

PY - 2015/2/18

Y1 - 2015/2/18

N2 - 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 caspase-8, RIPK3 kinase activity and MLKL are essential for TLR-induced NLRP3 activation. Consistent with in vitro experiments, interleukin-1 (IL-1)-dependent autoantibody-mediated arthritis is exacerbated in mice lacking IAPs, and is reduced by deletion of RIPK3, but not MLKL. Therefore RIPK3 can promote NLRP3 inflammasome and IL-1 β inflammatory responses independent of MLKL and necroptotic cell death.

AB - 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 caspase-8, RIPK3 kinase activity and MLKL are essential for TLR-induced NLRP3 activation. Consistent with in vitro experiments, interleukin-1 (IL-1)-dependent autoantibody-mediated arthritis is exacerbated in mice lacking IAPs, and is reduced by deletion of RIPK3, but not MLKL. Therefore RIPK3 can promote NLRP3 inflammasome and IL-1 β inflammatory responses independent of MLKL and necroptotic cell death.

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U2 - 10.1038/ncomms7282

DO - 10.1038/ncomms7282

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AN - SCOPUS:84923674191

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 6282

ER -

RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL

Abstract

Funding

UN SDGs

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