A common humanMLKLpolymorphism confers resistance to negative regulation by phosphorylation

Abstract

ABSTRACTAcross the globe, 2-3% of humans carry thep.Ser132Prosingle 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 MLKLS132Pin biological membranes and MLKLS132Poverriding pharmacological and endogenous inhibition of MLKL. In mouse cells, the equivalentMlkl S131Pmutation 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,MlklS131Phomozygosity reduces the capacity to clearSalmonellafrom 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 theMLKL S132Ppolymorphism may be the key to understanding how MLKL and necroptosis modulate the progression of complex polygenic human disease.