A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation

Sarah E. Garnish; Katherine R. Martin; Maria Kauppi; Victoria E. Jackson; Rebecca Ambrose; Vik Ven Eng; Shene Chiou; Yanxiang Meng; Daniel Frank; Emma C. Tovey Crutchfield; Komal M. Patel; Annette V. Jacobsen; Georgia K. Atkin-Smith; Ladina Di Rago; Marcel Doerflinger; Christopher R. Horne; Cathrine Hall; Samuel N. Young; Matthew Cook; Vicki Athanasopoulos; Carola G. Vinuesa; Kate E. Lawlor; Ian P. Wicks; Gregor Ebert; Ashley P. Ng; Charlotte A. Slade; Jaclyn S. Pearson; André L. Samson; John Silke; James M. Murphy; Joanne M. Hildebrand

doi:10.1038/s41467-023-41724-6

A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation

Sarah E. Garnish, Katherine R. Martin, Maria Kauppi, Victoria E. Jackson, Rebecca Ambrose, Vik Ven Eng, Shene Chiou, Yanxiang Meng, Daniel Frank, Emma C. Tovey Crutchfield, Komal M. Patel, Annette V. Jacobsen, Georgia K. Atkin-Smith, Ladina Di Rago, Marcel Doerflinger, Christopher R. Horne, Cathrine Hall, Samuel N. Young, Matthew Cook, Vicki AthanasopoulosCarola G. Vinuesa, Kate E. Lawlor, Ian P. Wicks, Gregor Ebert, Ashley P. Ng, Charlotte A. Slade, Jaclyn S. Pearson, André L. Samson, John Silke, James M. Murphy, Joanne M. Hildebrand^*

^*Corresponding author for this work

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

Abstract

Across the globe, 2-3% of humans carry the p.Ser132Pro single nucleotide polymorphism in MLKL, the terminal effector protein of the inflammatory form of programmed cell death, necroptosis. Here we show that this substitution confers a gain in necroptotic function in human cells, with more rapid accumulation of activated MLKL^S132P in biological membranes and MLKL^S132P overriding pharmacological and endogenous inhibition of MLKL. In mouse cells, the equivalent Mlkl S131P mutation confers a gene dosage dependent reduction in sensitivity to TNF-induced necroptosis in both hematopoietic and non-hematopoietic cells, but enhanced sensitivity to IFN-β induced death in non-hematopoietic cells. In vivo, Mlkl^S131P homozygosity reduces the capacity to clear Salmonella from major organs and retards recovery of hematopoietic stem cells. Thus, by dysregulating necroptosis, the S131P substitution impairs the return to homeostasis after systemic challenge. Present day carriers of the MLKL S132P polymorphism may be the key to understanding how MLKL and necroptosis modulate the progression of complex polygenic human disease.

Original language	English
Article number	6046
Number of pages	17
Journal	Nature Communications
Volume	14
DOIs	https://doi.org/10.1038/s41467-023-41724-6
Publication status	Published - 28 Sept 2023

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Solution structure of the MLKL N-terminal domain
Su, L. (Contributor), Rizo, J. (Contributor), Quade, B. (Contributor), Wang, H. (Contributor), Sun, L. (Contributor) & Wang, X. (Contributor), Protein Data Bank (PDB), 24 Sept 2014
DOI: 10.2210/pdb2MSV/pdb, https://doi.org/10.1042/BJ20131270 and one more link, https://doi.org/10.1016/j.immuni.2013.06.018 (show fewer)
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Garnish, S. E., Martin, K. R., Kauppi, M., Jackson, V. E., Ambrose, R., Eng, V. V., Chiou, S., Meng, Y., Frank, D., Tovey Crutchfield, E. C., Patel, K. M., Jacobsen, A. V., Atkin-Smith, G. K., Di Rago, L., Doerflinger, M., Horne, C. R., Hall, C., Young, S. N., Cook, M., ... Hildebrand, J. M. (2023). A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation. Nature Communications, 14, Article 6046. https://doi.org/10.1038/s41467-023-41724-6

@article{c4a381d91be14424a6695d7dd20d7691,

title = "A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation",

abstract = "Across the globe, 2-3% of humans carry the p.Ser132Pro single nucleotide polymorphism in MLKL, the terminal effector protein of the inflammatory form of programmed cell death, necroptosis. Here we show that this substitution confers a gain in necroptotic function in human cells, with more rapid accumulation of activated MLKLS132P in biological membranes and MLKLS132P overriding pharmacological and endogenous inhibition of MLKL. In mouse cells, the equivalent Mlkl S131P mutation confers a gene dosage dependent reduction in sensitivity to TNF-induced necroptosis in both hematopoietic and non-hematopoietic cells, but enhanced sensitivity to IFN-β induced death in non-hematopoietic cells. In vivo, MlklS131P homozygosity reduces the capacity to clear Salmonella from major organs and retards recovery of hematopoietic stem cells. Thus, by dysregulating necroptosis, the S131P substitution impairs the return to homeostasis after systemic challenge. Present day carriers of the MLKL S132P polymorphism may be the key to understanding how MLKL and necroptosis modulate the progression of complex polygenic human disease.",

author = "Garnish, {Sarah E.} and Martin, {Katherine R.} and Maria Kauppi and Jackson, {Victoria E.} and Rebecca Ambrose and Eng, {Vik Ven} and Shene Chiou and Yanxiang Meng and Daniel Frank and {Tovey Crutchfield}, {Emma C.} and Patel, {Komal M.} and Jacobsen, {Annette V.} and Atkin-Smith, {Georgia K.} and {Di Rago}, Ladina and Marcel Doerflinger and Horne, {Christopher R.} and Cathrine Hall and Young, {Samuel N.} and Matthew Cook and Vicki Athanasopoulos and Vinuesa, {Carola G.} and Lawlor, {Kate E.} and Wicks, {Ian P.} and Gregor Ebert and Ng, {Ashley P.} and Slade, {Charlotte A.} and Pearson, {Jaclyn S.} and Samson, {Andr{\'e} L.} and John Silke and Murphy, {James M.} and Hildebrand, {Joanne M.}",

note = "Funding: The authors are grateful to the National Health and Medical Research Council for fellowship (J.M.H., 1142669; A.L.S., 2002965; J.M.M., 1172929; J.S., 1107149), grant (J.M.M., 1105023; K.R.M., 1092602; J.S., 1105023; J.M.H., 2011584) and infrastructure (IRIISS 9000719); Arthritis Australia support to K.R.M; K.E.L funding by Future Fellowships from the ARC (FT19010266). We acknowledge scholarship support for S.E.G (Australian Government Research Training Program Stipend Scholarship; Wendy Dowsett Scholarship), Y.M (Melbourne Research Scholarship; AINSE PGRA Scholarship), D.F (Australian Government Research Training Program Stipend Scholarship), A.V.J (Australian Government Research Training Program Stipend Scholarship), and S.C (Walter and Eliza Hall Handman PhD Scholarship). Victorian State Government Operational Infrastructure Support Scheme.",

year = "2023",

month = sep,

day = "28",

doi = "10.1038/s41467-023-41724-6",

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature publishing group",

}

Garnish, SE, Martin, KR, Kauppi, M, Jackson, VE, Ambrose, R, Eng, VV, Chiou, S, Meng, Y, Frank, D, Tovey Crutchfield, EC, Patel, KM, Jacobsen, AV, Atkin-Smith, GK, Di Rago, L, Doerflinger, M, Horne, CR, Hall, C, Young, SN, Cook, M, Athanasopoulos, V, Vinuesa, CG, Lawlor, KE, Wicks, IP, Ebert, G, Ng, AP, Slade, CA, Pearson, JS, Samson, AL, Silke, J, Murphy, JM & Hildebrand, JM 2023, 'A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation', Nature Communications, vol. 14, 6046. https://doi.org/10.1038/s41467-023-41724-6

TY - JOUR

T1 - A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation

AU - Garnish, Sarah E.

AU - Martin, Katherine R.

AU - Kauppi, Maria

AU - Jackson, Victoria E.

AU - Ambrose, Rebecca

AU - Eng, Vik Ven

AU - Chiou, Shene

AU - Meng, Yanxiang

AU - Frank, Daniel

AU - Tovey Crutchfield, Emma C.

AU - Patel, Komal M.

AU - Jacobsen, Annette V.

AU - Atkin-Smith, Georgia K.

AU - Di Rago, Ladina

AU - Doerflinger, Marcel

AU - Horne, Christopher R.

AU - Hall, Cathrine

AU - Young, Samuel N.

AU - Cook, Matthew

AU - Athanasopoulos, Vicki

AU - Vinuesa, Carola G.

AU - Lawlor, Kate E.

AU - Wicks, Ian P.

AU - Ebert, Gregor

AU - Ng, Ashley P.

AU - Slade, Charlotte A.

AU - Pearson, Jaclyn S.

AU - Samson, André L.

AU - Silke, John

AU - Murphy, James M.

AU - Hildebrand, Joanne M.

N1 - Funding: The authors are grateful to the National Health and Medical Research Council for fellowship (J.M.H., 1142669; A.L.S., 2002965; J.M.M., 1172929; J.S., 1107149), grant (J.M.M., 1105023; K.R.M., 1092602; J.S., 1105023; J.M.H., 2011584) and infrastructure (IRIISS 9000719); Arthritis Australia support to K.R.M; K.E.L funding by Future Fellowships from the ARC (FT19010266). We acknowledge scholarship support for S.E.G (Australian Government Research Training Program Stipend Scholarship; Wendy Dowsett Scholarship), Y.M (Melbourne Research Scholarship; AINSE PGRA Scholarship), D.F (Australian Government Research Training Program Stipend Scholarship), A.V.J (Australian Government Research Training Program Stipend Scholarship), and S.C (Walter and Eliza Hall Handman PhD Scholarship). Victorian State Government Operational Infrastructure Support Scheme.

PY - 2023/9/28

Y1 - 2023/9/28

N2 - Across the globe, 2-3% of humans carry the p.Ser132Pro single nucleotide polymorphism in MLKL, the terminal effector protein of the inflammatory form of programmed cell death, necroptosis. Here we show that this substitution confers a gain in necroptotic function in human cells, with more rapid accumulation of activated MLKLS132P in biological membranes and MLKLS132P overriding pharmacological and endogenous inhibition of MLKL. In mouse cells, the equivalent Mlkl S131P mutation confers a gene dosage dependent reduction in sensitivity to TNF-induced necroptosis in both hematopoietic and non-hematopoietic cells, but enhanced sensitivity to IFN-β induced death in non-hematopoietic cells. In vivo, MlklS131P homozygosity reduces the capacity to clear Salmonella from major organs and retards recovery of hematopoietic stem cells. Thus, by dysregulating necroptosis, the S131P substitution impairs the return to homeostasis after systemic challenge. Present day carriers of the MLKL S132P polymorphism may be the key to understanding how MLKL and necroptosis modulate the progression of complex polygenic human disease.

AB - Across the globe, 2-3% of humans carry the p.Ser132Pro single nucleotide polymorphism in MLKL, the terminal effector protein of the inflammatory form of programmed cell death, necroptosis. Here we show that this substitution confers a gain in necroptotic function in human cells, with more rapid accumulation of activated MLKLS132P in biological membranes and MLKLS132P overriding pharmacological and endogenous inhibition of MLKL. In mouse cells, the equivalent Mlkl S131P mutation confers a gene dosage dependent reduction in sensitivity to TNF-induced necroptosis in both hematopoietic and non-hematopoietic cells, but enhanced sensitivity to IFN-β induced death in non-hematopoietic cells. In vivo, MlklS131P homozygosity reduces the capacity to clear Salmonella from major organs and retards recovery of hematopoietic stem cells. Thus, by dysregulating necroptosis, the S131P substitution impairs the return to homeostasis after systemic challenge. Present day carriers of the MLKL S132P polymorphism may be the key to understanding how MLKL and necroptosis modulate the progression of complex polygenic human disease.

U2 - 10.1038/s41467-023-41724-6

DO - 10.1038/s41467-023-41724-6

M3 - Article

C2 - 37770424

AN - SCOPUS:85173103743

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

M1 - 6046

ER -

A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation

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Solution structure of the MLKL N-terminal domain

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