1. Pore-forming Staphylococcus aureus alpha-toxin triggers epidermal growth factor receptor-dependent proliferation.
- Author
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Haugwitz U, Bobkiewicz W, Han SR, Beckmann E, Veerachato G, Shaid S, Biehl S, Dersch K, Bhakdi S, and Husmann M
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Blotting, Western, Cell Cycle, Cell Line, Cell Line, Transformed, Cell Proliferation, Cytotoxins metabolism, Flow Cytometry, Fluorescent Antibody Technique, Gene Expression Profiling, Humans, Keratinocytes cytology, Keratinocytes microbiology, Mitogens pharmacology, Reverse Transcriptase Polymerase Chain Reaction, Shc Signaling Adaptor Proteins, Signal Transduction, Src Homology 2 Domain-Containing, Transforming Protein 1, Transfection, Bacterial Toxins, ErbB Receptors metabolism, Hemolysin Proteins, Keratinocytes metabolism, Staphylococcus aureus physiology
- Abstract
Staphylococcal alpha-toxin is an archetypal killer protein that homo-oligomerizes in target cells to create small transmembrane pores. The membrane-perforating beta-barrel motif is a conserved attack element of cytolysins of Gram-positive and Gram-negative bacteria. Following the recognition that nucleated cells can survive membrane permeabilization, a profile of abundant transcripts was obtained in transiently perforated keratinocytes. Several immediate early genes were found to be upregulated, reminiscent of the cellular response to growth factors. Cell cycle analyses revealed doubling of S + G2/M phase cells 26 h post toxin treatment. Determination of cell counts uncovered that after an initial drop, numbers increased to exceed the controls after 2 days. A non-lytic alpha-toxin mutant remained without effect. The alpha-toxin pore is too small to allow egress of cytosolic growth factors, and evidence was instead obtained for growth signalling via the epidermal growth factor receptor (EGFR). Inhibition of the EGFR or of EGFR-proligand-processing blocked the mitogenic effect of alpha-toxin. Western blots with phospho-specific antibodies revealed activation of the EGFR, and of the adapter protein Shc. Immediate early response and proliferation upon transient plasma membrane pore formation by bacterial toxins may represent a novel facet of the complex interaction between pathogen and host.
- Published
- 2006
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