title: Staphylococcus aureus protein A activates TACE through EGFR-dependent signaling.
abstract: 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.
authors.affiliation: Department of Pediatrics and Pharmacology, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA. asp7@columbia.edu
authors.forename: Marisa I
authors.initials: MI
authors.lastname: Gómez
authors.forename: Maghnus O
authors.initials: MO
authors.lastname: Seaghdha
authors.forename: Alice S
authors.initials: AS
authors.lastname: Prince
mesh_terms: 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*
chemical_list: 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