Staphylococcus aureus protein A activates TACE through EGFR-dependent signaling
Staphylococcus aureus protein A activates TACE through EGFR-dependent signaling
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DOI：
10.1038/sj.emboj.7601554
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发表时间：
2007-02-07
期刊：
影响因子：
11.4
通讯作者：
Prince, Alice S.
中科院分区：
文献类型：
--
作者：
Gomez, Marisa I.;O Seaghdha, Maghnus;Prince, Alice S.
在金黄色葡萄球菌表达的许多粘附素和毒素中，蛋白A是一种异常复杂的毒力因子，已知可与多种真核靶标相互作用，特别是具有免疫功能的靶标。蛋白A作为一种配体，可以模仿tnf - α激活TNFR1和随后的促炎信号。它还刺激上皮细胞和巨噬细胞表面TNFR1的分裂，这有助于限制tnf - α信号传导。我们鉴定了负责TNFR1脱落的信号通路，并鉴定了可以激活TNFR1依赖性信号通路，但不能激活TACE （TNFR1脱落酶）的蛋白A突变体。TACE的激活依赖于先前定义的蛋白a的igg结合域和表皮生长因子受体（EGFR）之间的离散相互作用，后者反过来通过c- src -erk1/2介导的级联诱导TACE磷酸化。这种新的相互作用独立于EGFR的自分泌激活，而蛋白a诱导的tgf - α既不需要也不足以激活TNFR1的脱落。因此，葡萄球菌利用无处不在的多功能EGFR来调节TNFR1在粘膜和免疫细胞上的可用性。
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.