A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation
Garnish, S. E.; Martin, K. R.; Kauppi, M.; Jackson, V.; Ambrose, R.; Eng, V. V.; Frank, D.; Tovey Crutchfield, E. C.; Patel, K. M.; Chiou, S.; Samson, A. L.; Doerflinger, M.; Horne, C. R.; Hall, C.; Young, S. N.; Athanasopoulos, V.; Vinuesa, C. G.; Slade, C. A.; Pearson, J. S.; Ebert, G.; Silke, J.; Murphy, J. M.; Hildebrand, J.
Show 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. 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 MLKLS132P 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, MlklS131P 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.
Matching journals
The top 2 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
Similar papers in this journal
- Convergent evolution of monocyte differentiation in adult skin instructs Langerhans cell identity 95%
- Invasion of spontaneous germinal centers by naive B cells is rapid and persistent 95%
- Evolution-inspired dissection of caspase activities enables the redesign of caspase-4 into an LPS sensing interleukin-1 converting enzyme 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.