Program in Molecular Medicine
Bacteriology | Immunity | Immunopathology | Pathogenic Microbiology
We report on the role of conserved stress-response pathways for cellular tolerance to a pore forming toxin. First, we observed that small molecular weight inhibitors including of eIF2alpha-phosphatase, jun-N-terminal kinase (JNK), and PI3-kinase sensitized normal mouse embryonal fibroblasts (MEFs) to the small pore forming S. aureus alpha-toxin. Sensitization depended on expression of mADAM10, the murine ortholog of a proposed high-affinity receptor for alpha-toxin in human cells. Similarly, eIF2alpha (S51A/S51A) MEFs, which harbor an Ala knock-in mutation at the regulated Ser51 phosphorylation site of eukaryotic translation initiation factor 2alpha, were hyper-sensitive to alpha-toxin. Inhibition of translation with cycloheximide did not mimic the tolerogenic effect of eIF2alpha-phosphorylation. Notably, eIF2alpha-dependent tolerance of MEFs was toxin-selective, as wild-type MEFs and eIF2alpha (S51A/S51A) MEFs exhibited virtually equal sensitivity to Vibrio cholerae cytolysin. Binding of S. aureus alpha-toxin to eIF2alpha (S51A/S51A) MEFs and toxicity in these cells were enhanced as compared to wild-type cells. This led to the unexpected finding that the mutant cells carried more ADAM10. Because basal phosphorylation of eIF2alpha in MEFs required amino acid deprivation-activated eIF2alpha-kinase 4/GCN2, the data reveal that basal activity of this kinase mediates tolerance of MEFs to alpha-toxin. Further, they suggest that modulation of ADAM10 is involved. During infection, bacterial growth may cause nutrient shortage in tissues, which might activate this response. Tolerance to alpha-toxin was robust in macrophages and did not depend on GCN2. However, JNKs appeared to play a role, suggesting differential cell type and toxin selectivity of tolerogenic stress responses. Understanding their function or failure will be important to comprehend anti-bacterial immune responses.
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Citation: Front Immunol. 2015 Jul 27;6:383. doi: 10.3389/fimmu.2015.00383. eCollection 2015. Link to article on publisher's site
DOI of Published Version
EIF2AK4, MAPK, S. aureus α-toxin, cellular tolerance, pore forming toxins
Frontiers in immunology
von Hoven, Gisela; Neukirch, Claudia; Meyenburg, Martina; Fuser, Sabine; Petrivna, Maria Bidna; Rivas, Amable J.; Ryazanov, Alexey; Kaufman, Randal J.; Aroian, Raffi V.; and Husmann, Matthias, "eIF2alpha Confers Cellular Tolerance to S. aureus alpha-Toxin" (2015). Open Access Articles. 2730.
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