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 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

SUBMITTER: Garnish SE 

PROVIDER: S-EPMC10539340 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature