Staphylococcus aureus protein A activates TACE through EGFR-dependent signaling

被引:77
作者
Gomez, Marisa I.
O Seaghdha, Maghnus
Prince, Alice S.
机构
[1] Columbia Univ, Coll Phys & Surg, Dept Pediat & Pharmacol, New York, NY 10032 USA
[2] Trinity Coll Dublin, Moyne Inst Preventat Med, Dept Microbiol, Dublin, Ireland
关键词
EGFR; S. aureus protein A; shedding; TACE; TNFR1;
D O I
10.1038/sj.emboj.7601554
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:701 / 709
页数:9
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