| First Author | Garnish SE | Year | 2023 |
| Journal | Nat Commun | Volume | 14 |
| Issue | 1 | Pages | 6046 |
| PubMed ID | 37770424 | Mgi Jnum | J:358259 |
| Mgi Id | MGI:7538359 | Doi | 10.1038/s41467-023-41724-6 |
| Citation | Garnish SE, et al. (2023) A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation. Nat Commun 14(1):6046 |
| abstractText | 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. |
