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 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 and Joanne M. Hildebrand ()
Additional contact information
Sarah E. Garnish: The Walter and Eliza Hall Institute
Katherine R. Martin: The Walter and Eliza Hall Institute
Maria Kauppi: The Walter and Eliza Hall Institute
Victoria E. Jackson: The Walter and Eliza Hall Institute
Rebecca Ambrose: Hudson Institute of Medical Research
Vik Ven Eng: Hudson Institute of Medical Research
Shene Chiou: The Walter and Eliza Hall Institute
Yanxiang Meng: The Walter and Eliza Hall Institute
Daniel Frank: The Walter and Eliza Hall Institute
Emma C. Tovey Crutchfield: The Walter and Eliza Hall Institute
Komal M. Patel: The Walter and Eliza Hall Institute
Annette V. Jacobsen: The Walter and Eliza Hall Institute
Georgia K. Atkin-Smith: The Walter and Eliza Hall Institute
Ladina Rago: The Walter and Eliza Hall Institute
Marcel Doerflinger: The Walter and Eliza Hall Institute
Christopher R. Horne: The Walter and Eliza Hall Institute
Cathrine Hall: The Walter and Eliza Hall Institute
Samuel N. Young: The Walter and Eliza Hall Institute
Matthew Cook: Australian National University
Vicki Athanasopoulos: Australian National University
Carola G. Vinuesa: Australian National University
Kate E. Lawlor: Hudson Institute of Medical Research
Ian P. Wicks: The Walter and Eliza Hall Institute
Gregor Ebert: Technical University of Munich/Helmholtz Munich
Ashley P. Ng: The Walter and Eliza Hall Institute
Charlotte A. Slade: The Walter and Eliza Hall Institute
Jaclyn S. Pearson: Hudson Institute of Medical Research
André L. Samson: The Walter and Eliza Hall Institute
John Silke: The Walter and Eliza Hall Institute
James M. Murphy: The Walter and Eliza Hall Institute
Joanne M. Hildebrand: The Walter and Eliza Hall Institute

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41724-6

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