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 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.

在全球范围内，2-3% 的人携带MLKL中的p.Ser132Pro单核苷酸多态性，MLKL 是程序性细胞死亡炎症形式坏死性凋亡的终末效应蛋白。^{在这里，我们表明，这种取代赋予人类细胞坏死性凋亡功能，激活的 MLKL S132P}在生物膜中更快积累，并且 MLKL ^S132P超越 MLKL 的药理学和内源性抑制。在小鼠细胞中，等效的Mlkl S131P突变使造血细胞和非造血细胞对TNF诱导的坏死性凋亡的敏感性呈基因剂量依赖性降低，但在非造血细胞中增强对IFN-β诱导的死亡的敏感性。在体内，Mlkl ^S131P纯合性降低了从主要器官中清除沙门氏菌的能力，并阻碍了造血干细胞的恢复。因此，通过失调坏死性凋亡，S131P 替代会损害全身挑战后体内平衡的恢复。目前MLKL S132P多态性的携带者可能是了解 MLKL 和坏死性凋亡如何调节复杂多基因人类疾病进展的关键。