A common human MLKL polymorphism confers resistance 1 to negative regulation by phosphorylation

Across the globe, 2-3% of humans carry the p.Ser132Pro single nucleotide polymorphism inMLKL, the terminal effector protein of the inflammatory form of programmed cell death,necroptosis. 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 MLKLS132Poverriding pharmacological and endogenous inhibition of MLKL. In mouse cells, the equivalentMlkl S131P mutation confers a gene dosage dependent reduction in sensitivity to TNF-inducednecroptosis in both hematopoietic and non-hematopoietic cells, but enhanced sensitivity to IFN-Betainduced death in non-hematopoietic cells. In vivo, MlklS131P homozygosity reduces the capacity toclear Salmonella from major organs and retards recovery of hematopoietic stem cells. Thus, bydysregulating necroptosis, the S131P substitution impairs the return to homeostasis after systemicchallenge. Present day carriers of the MLKL S132P polymorphism may be the key to understandinghow MLKL and necroptosis modulate the progression of complex polygenic human disease.