Impact of structural polymorphism for the Helicobacter pylori CagA oncoprotein on binding to polarity-regulating kinase PAR1b.
Impact of structural polymorphism for the Helicobacter pylori CagA oncoprotein on binding to polarity-regulating kinase PAR1b.
复制标题
DOI：
10.1038/srep30031
复制
发表时间：
2016-07-22
影响因子：
4.6
通讯作者：
Hatakeyama M
中科院分区：
文献类型：
--
作者：
Nishikawa H;Hayashi T;Arisaka F;Senda T;Hatakeyama M
慢性感染cagA阳性的幽门螺杆菌是萎缩性胃炎、消化性溃疡和胃癌的最大危险因素。CagA是cagA基因的产物，是一种细菌癌蛋白，在进入胃上皮细胞后，通过其CagA多聚化(CM)基序与极性调节蛋白1b(PAR1b)[也称为微管亲和力调节蛋白2(Mark2)]结合并抑制。抑制PAR1b会引起连接和极性缺陷，使细胞更容易发生肿瘤。值得注意的是，CM基序的多态已经在CagA的地理变体中被鉴定出来，无论是在拷贝数上还是在序列组成上都不同。在本研究中，通过对CagA和PAR1b之间的络合物形成的定量分析，我们发现一些CagA物种通过复制CM基序获得了高水平的PAR1b结合活性，而另一些物种则失去了PAR1b结合活性。我们还发现，CagA-PAR1b相互作用的强度与CagA在胃上皮细胞中形成应力纤维和紧密连接破坏的程度成正比。这些结果表明，CM多态是CagA介导的细胞骨架系统失调程度的决定因素，因此可能影响包括胃癌在内的cagA阳性幽门螺杆菌感染的疾病结局。
Chronic infection with cagA-positive Helicobacter pylori is the strongest risk factor for atrophic gastritis, peptic ulcers, and gastric cancer. CagA, the product of the cagA gene, is a bacterial oncoprotein, which, upon delivery into gastric epithelial cells, binds to and inhibits the polarity-regulating kinase, partitioning-defective 1b (PAR1b) [also known as microtubule affinity-regulating kinase 2 (MARK2)], via its CagA multimerization (CM) motif. The inhibition of PAR1b elicits junctional and polarity defects, rendering cells susceptible to oncogenesis. Notably, the polymorphism in the CM motif has been identified among geographic variants of CagA, differing in either the copy number or the sequence composition. In this study, through quantitative analysis of the complex formation between CagA and PAR1b, we found that several CagA species have acquired elevated PAR1b-binding activity via duplication of the CM motifs, while others have lost their PAR1b-binding activity. We also found that strength of CagA-PAR1b interaction was proportional to the degrees of stress fiber formation and tight junctional disruption by CagA in gastric epithelial cells. These results indicate that the CM polymorphism is a determinant for the magnitude of CagA-mediated deregulation of the cytoskeletal system and thereby possibly affects disease outcome of cagA-positive H. pylori infection, including gastric cancer.