Pore-forming Staphylococcus aureus ?-toxin triggers epidermal growth factor receptor-dependent proliferation
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.
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Hla stimulates epithelial proliferation via EGFR, so keratinocyte infection results in focal areas of infection and induction of more keratinocytes rather than widespread loss of barrier function.
“As S. aureus Hla stimulates epithelial proliferation via EGFR [15], keratinocyte infection does not result in widespread loss of barrier function but instead results in focal areas of infection and induction of more keratinocytes to replace the necrotic cells.”
From Staphylococcus aureus activation of caspase 1/calpain signaling mediates invasion through human keratinocytes (2012) · cites this paper as [15]
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- Authors
- Haugwitz, U., Bobkiewicz, W., Han, S.-R., Beckmann, E., Veerachato, G., Shaid, S., Biehl, S., Dersch, K., Bhakdi, S., & Husmann, M.
- Affiliations
- Johannes Gutenberg University Mainz (DE)
- Corresponding author
- Husmann, Matthias
- ORCID
- Beckmann, Erik
- Venue
- Cellular Microbiology
- Publisher
- Hindawi Limited
- Published
- 2006-10
- Volume
- 8
- Issue
- 10
- Pages
- 1591-1600
- ISSN
- 1462-5814 (ISSN-L)
- 1462-5822
- OpenAlex
- W1975587028
- Cited by
- 58
- References
- 42
- Citations by year
- 2024: 1 · 2023: 2 · 2022: 2 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 5 · 2016: 6 · 2015: 9 · 2014: 3 · 2013: 5 · 2012: 5
- FWCI
- 1.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cellular Microbiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antimicrobial Resistance in Staphylococcus
- Life Sciences › Immunology and Microbiology › Immunology › Toxin Mechanisms and Immunotoxins
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- Staphylococcus aureus alpha-toxin, cytolysin, pore formation, epidermal growth factor receptor, keratinocyte proliferation, EGFR signaling, Shc adapter protein, immediate early gene expression, host-pathogen interaction, cell cycle
- MeSH terms
- Src Homology 2 Domain-Containing, Transforming Protein 1, Bacterial Toxins, Cell Cycle, Cell Line, Cell Line, Transformed, Cytotoxins, Flow Cytometry, Fluorescent Antibody Technique, Hemolysin Proteins, Humans, Mitogens, Staphylococcus aureus, Transfection, Blotting, Western, Signal Transduction, Keratinocytes, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Adaptor Proteins, Signal Transducing, Cell Proliferation, Shc Signaling Adaptor Proteins, ErbB Receptors
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