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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.* ; Athanasopoulos, V.* ; Vinuesa, C.G.* ; Lawlor, K.E.* ; Wicks, I.P.* ; Ebert, G. ; Ng, A.P.* ; Slade, C.A.* ; Pearson, J.S.* ; Samson, A.L.* ; Silke, J.* ; Murphy, J.M.* ; Hildebrand, J.M.*

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

Nat. Commun. 14:6046 (2023)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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, 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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 14, Issue: 1, Pages: , Article Number: 6046 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Virology (VIRO)