Staphylococcus aureus protein A activates TACE through EGFR-dependent signaling.
Among the many adhesins and toxins expressed by Staphylococcus aureus, protein A is an exceptionally complex virulence factor, known to interact with multiple eukaryotic targets, particularly those with immunological functions. Protein A acts as a ligand that can mimic TNF-alpha to activate TNFR1 and subsequent proinflammatory signaling. It also stimulates the cleavage of TNFR1 from the surface of epithelial cells and macrophages, which serves to limit TNF-alpha signaling. We characterized the signaling pathway responsible for TNFR1 shedding and identified protein A mutants which could activate TNFR1-dependent signaling, but were unable to activate TACE, the TNFR1 sheddase. Activation of TACE was dependent upon a discrete interaction between the previously defined IgG-binding domain of protein A and the epidermal growth factor receptor (EGFR), which in turn induced TACE phosphorylation through a c-Src-erk1/2-mediated cascade. This novel interaction was independent of the autocrine activation of EGFR and protein A-induced TGF-alpha was neither required nor sufficient to activate TNFR1 shedding. Thus, staphylococci exploit the ubiquitous and multifunctional EGFR to regulate the availability of TNFR1 on mucosal and immune cells.
Gómez
Marisa I
MI
Department of Pediatrics and Pharmacology, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA. asp7@columbia.edu
Seaghdha
Maghnus O
MO
Prince
Alice S
AS
D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D015153:Blotting, Western; D017931:DNA Primers; D004789:Enzyme Activation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000378:metabolism*; D005434:Flow Cytometry; D047468:Immunoprecipitation; D016209:Interleukin-8 / Q000378:metabolism; D010766:Phosphorylation; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013205:Staphylococcal Protein A / Q000235:genetics / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000235:genetics* / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; D016209:Interleukin-8; D047888:Receptors, Tumor Necrosis Factor, Type I; D013205:Staphylococcal Protein A; D016211:Transforming Growth Factor alpha; D037521:Virulence Factors; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein