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.
EIF2AK4, MAPK, S. aureus α-toxin, cellular tolerance, pore forming toxins
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Copyright © 2015 von Hoven, Neukirch, Meyenburg, Füser, Petrivna, Rivas, Ryazanov, Kaufman, Aroian and Husmann. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
DOI of Published Version
Front Immunol. 2015 Jul 27;6:383. doi: 10.3389/fimmu.2015.00383. eCollection 2015. Link to article on publisher's site
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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