Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Minato-ku, Tokyo, Japan.
PLoS One. 2011;6(8):e23499. doi: 10.1371/journal.pone.0023499. Epub 2011 Aug 11.
Helicobacter pylori is a gastric pathogen that infects half the human population and causes gastritis, ulcers, and cancer. The cagA gene product is a major virulence factor associated with gastric cancer. It is injected into epithelial cells, undergoes phosphorylation by host cell kinases, and perturbs host signaling pathways. CagA is known for its geographical, structural, and functional diversity in the C-terminal half, where an EPIYA host-interacting motif is repeated. The Western version of CagA carries the EPIYA segment types A, B, and C, while the East Asian CagA carries types A, B, and D and shows higher virulence. Many structural variants such as duplications and deletions are reported. In this study, we gained insight into the relationships of CagA variants through various modes of recombination, by analyzing all known cagA variants at the DNA sequence level with the single nucleotide resolution. Processes that occurred were: (i) homologous recombination between DNA sequences for CagA multimerization (CM) sequence; (ii) recombination between DNA sequences for the EPIYA motif; and (iii) recombination between short similar DNA sequences. The left half of the EPIYA-D segment characteristic of East Asian CagA was derived from Western type EPIYA, with Amerind type EPIYA as the intermediate, through rearrangements of specific sequences within the gene. Adaptive amino acid changes were detected in the variable region as well as in the conserved region at sites to which no specific function has yet been assigned. Each showed a unique evolutionary distribution. These results clarify recombination-mediated routes of cagA evolution and provide a solid basis for a deeper understanding of its function in pathogenesis.
幽门螺杆菌是一种胃部病原体，感染了全球一半的人口，导致胃炎、溃疡和癌症。cagA 基因产物是与胃癌相关的主要毒力因子。它被注射到上皮细胞中，被宿主细胞激酶磷酸化，并扰乱宿主信号通路。CagA 因其在 C 端的地理、结构和功能多样性而闻名，其中重复了一个 EPIYA 宿主相互作用基序。西方型 CagA 携带 EPIYA 片段 A、B 和 C 型，而东亚型 CagA 携带 A、B 和 D 型，显示出更高的毒力。已经报道了许多结构变异，如重复和缺失。在这项研究中，我们通过单核苷酸分辨率分析所有已知的 cagA 变体的 DNA 序列水平，深入了解了 CagA 变体的关系，通过各种重组模式。发生的过程包括：（i）CagA 多聚化（CM）序列的 DNA 序列之间的同源重组；（ii）EPIYA 基序的 DNA 序列之间的重组；（iii）短相似 DNA 序列之间的重组。东亚型 CagA 的 EPIYA-D 片段的左半部分来源于西方型 EPIYA，其中间是美洲型 EPIYA，通过基因内特定序列的重排。在可变区和尚未赋予特定功能的保守区都检测到适应性氨基酸变化。每个都显示出独特的进化分布。这些结果阐明了 cagA 进化的重组介导途径，并为更深入了解其在发病机制中的功能提供了坚实的基础。
