Pore-forming Staphylococcus aureus α-toxin triggers epidermal growth factor receptor-dependent proliferation
Pore-forming Staphylococcus aureus α-toxin triggers epidermal growth factor receptor-dependent proliferation
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DOI：
10.1111/j.1462-5822.2006.00733.x
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发表时间：
2006-10-01
影响因子：
3.4
通讯作者：
Husmann, Matthias
中科院分区：
文献类型：
--
作者：
Haugwitz, Ulrike;Bobkiewicz, Wiesia;Husmann, Matthias
葡萄球菌α毒素是一种原型杀伤蛋白，其在靶细胞中同源寡聚化以产生小的跨膜孔。膜穿孔β-桶基序是革兰氏阳性菌和革兰氏阴性菌溶细胞素的保守攻击元件。认识到有核细胞可以在膜透化中存活后，在瞬时穿孔的角质形成细胞中获得了丰富的转录本。几个立即早期基因被发现上调，让人想起细胞对生长因子的反应。细胞周期分析显示毒素处理后26 h S + G（2）/M期细胞加倍。细胞计数的测定发现，在初始下降后，2天后数量增加至超过对照组。非裂解性α-毒素突变体仍然没有效果。α-毒素孔太小而不允许胞质生长因子流出，并且相反获得了通过表皮生长因子受体（EGFR）的生长信号传导的证据。抑制EGFR或EGFR前配体加工阻断了α毒素的促有丝分裂作用。用磷酸特异性抗体进行的蛋白质印迹显示EGFR和接头蛋白Shc的活化。细菌毒素对瞬时质膜孔形成的即时早期反应和增殖可能代表了病原体与宿主之间复杂相互作用的一个新方面。
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 + G(2)/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.