A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation
Details
Publication Year 2023-09-28,Volume 14,Issue #1,Page 6046
Journal Title
Nature Communications
Publication Type
Research article
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-beta 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.
Publisher
Springer Nature
Keywords
Humans; Animals; Mice; Phosphorylation; *Protein Kinases/genetics/metabolism; *Apoptosis; Cell Membrane/metabolism; Mutation; Transcription Factors/metabolism; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism
Department(s)
Clinical Haematology
PubMed ID
37770424
Open Access at Publisher's Site
https://doi.org/10.1038/s41467-023-41724-6
Terms of Use/Rights Notice
Refer to copyright notice on published article.


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Last Modified: 2023-11-15 02:59:05

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