Pore-forming Staphylococcus aureus alpha-toxin triggers epidermal growth factor receptor-dependent proliferation.
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.
Haugwitz
Ulrike
U
Institute of Medical Microbiology and Hygiene, Johannes Gutenberg-University, Hochhaus am Augustusplatz, Mainz, Germany.
Bobkiewicz
Wiesia
W
Han
Shan-Rui
SR
Beckmann
Erik
E
Veerachato
Gunnaporn
G
Shaid
Shabnam
S
Biehl
Saskia
S
Dersch
Katrin
K
Bhakdi
Sucharit
S
Husmann
Matthias
M
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001427:Bacterial Toxins; D015153:Blotting, Western; D002453:Cell Cycle; D002460:Cell Line; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D003603:Cytotoxins / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D006460:Hemolysin Proteins; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism* / Q000382:microbiology; D008934:Mitogens / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013211:Staphylococcus aureus / Q000502:physiology*; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D001427:Bacterial Toxins; D003603:Cytotoxins; D006460:Hemolysin Proteins; D008934:Mitogens; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C021091:staphylococcal alpha-toxin; D066246:ErbB Receptors