Functional antagonism between Helicobacter pylori CagA and vacuolating toxin VacA in control of the NFAT signaling pathway in gastric epithelial cells.
Functional antagonism between Helicobacter pylori CagA and vacuolating toxin VacA in control of the NFAT signaling pathway in gastric epithelial cells.
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DOI：
10.1073/pnas.0502529102
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发表时间：
2005-07
影响因子：
11.1
通讯作者：
Kazuyuki Yokoyama;H. Higashi;S. Ishikawa;Y. Fujii;S. Kondo;H. Kato;T. Azuma;A. Wada;T. Hirayama;H. Aburatani;M. Hatakeyama
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文献类型：
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作者：
Kazuyuki Yokoyama;H. Higashi;S. Ishikawa;Y. Fujii;S. Kondo;H. Kato;T. Azuma;A. Wada;T. Hirayama;H. Aburatani;M. Hatakeyama
感染cagA阳性的幽门螺杆菌引发的慢性感染与萎缩性胃炎、消化性溃疡以及胃腺癌的发生相关。cagA基因产物CagA会被注入胃上皮细胞，在那里它会被Src家族激酶进行酪氨酸磷酸化。转位的CagA通过与细胞内信号转导分子发生物理相互作用，并通过酪氨酸磷酸化依赖及非依赖机制对其进行异常调节，从而扰乱细胞功能。为了更深入了解CagA在胃上皮细胞中的病理生理活动，我们利用DNA微阵列对CagA应答基因进行了全基因组筛选，并确定了活化T细胞核因子（NFAT）转录因子，其结合位点在CagA激活基因的启动子区域中显著富集。报告基因检测结果证实，CagA能够以不依赖于CagA磷酸化的方式激活NFAT。CagA在胃上皮细胞中的表达促使NFAT家族成员NFATc3从细胞质转位至细胞核，并激活了NFAT调控基因p21WAF1/Cip1。抑制钙调神经磷酸酶或磷脂酶Cγ的活性，可消除CagA介导的NFAT激活。此外，用幽门螺杆菌空泡毒素（VacA，可抑制T淋巴细胞中的NFAT活性）处理细胞，会抵消CagA激活胃上皮细胞中NFAT的能力。这些研究结果表明，幽门螺杆菌的这两种主要毒力因子对NFAT活性起着相反的调控作用。鉴于NFAT在细胞生长和分化中具有多效性作用，根据细胞对CagA和VacA的相对暴露情况，NFAT的正向或负向失调可能导致幽门螺杆菌感染引发的各种疾病结局。
Chronic infection with cagA-positive Helicobacter pylori is associated with the development of atrophic gastritis, peptic ulcers, and gastric adenocarcinoma. The cagA gene product CagA is injected into gastric epithelial cells, where it undergoes tyrosine phosphorylation by Src family kinases. Translocated CagA disturbs cellular functions by physically interacting with and deregulating intracellular signaling transducers through both tyrosine phosphorylation-dependent and -independent mechanisms. To gain further insights into the pathophysiological activities of CagA in gastric epithelial cells, we executed a genome-wide screening of CagA-responsive genes by using DNA microarray and identified nuclear factor of activated T cells (NFAT) transcription factors whose binding sites were overrepresented in the promoter regions of CagA-activated genes. Results of reporter assays confirmed that CagA was capable of activating NFAT in a manner independent of CagA phosphorylation. Expression of CagA in gastric epithelial cells provoked translocation of NFATc3, a member of the NFAT family, from the cytoplasm to the nucleus and activated an NFAT-regulated gene, p21WAF1/Cip1. CagA-mediated NFAT activation was abolished by inhibiting calcineurin or phospholipase Cgamma activity. Furthermore, treatment of cells with H. pylori VacA (vacuolating toxin), which inhibits NFAT activity in T lymphocytes, counteracted the ability of CagA to activate NFAT in gastric epithelial cells. These findings indicate that the two major H. pylori virulence factors inversely control NFAT activity. Considering the pleiotropic roles of NFAT in cell growth and differentiation, deregulation of NFAT, either positively or negatively, depending on the relative exposure of cells to CagA and VacA, may contribute to the various disease outcomes caused by H. pylori infection.