biostudies-literatureGarnish SEDepartment of Health | National Health and Medical Research Council6046https://www.ebi.ac.uk/biostudies/studies/S-EPMC10539340biostudies-literatureUnknown14(1)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 Nature communicationsA common human MLKL polymorphism confers resistance to negative regulation by phosphorylation.PMC10539340110502311071492002965109260211426692011584Horne CRYoung SNLawlor KEPearson JSSilke JKauppi MMeng YSlade CATovey Crutchfield ECFrank DJacobsen AVPatel KMMartin KREng VVVinuesa CGDoerflinger MHall CGarnish SEChiou SAmbrose RAtkin-Smith GKNg APSamson ALCook MWicks IPAthanasopoulos VHildebrand JMMurphy JMDi Rago LEbert GJackson VEfalseA common human MLKL polymorphism confers resistance to negative regulation by phosphorylation.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 2023-01-01T00:00:00Z2023 Sep2026-05-29T01:58:13.345Z2024-12-03T23:39:04.303ZS-EPMC105393403777042410.1038/s41467-023-41724-6