Gu Jiayu, Guo Yunxue, Weng Juehua, Lin Shituan, Liu Yabo, Wang Xiaoxue
State Key Laboratory of Tropical Oceanography, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, China.
University of Chinese Academy of Sciences, Beijing, China.
Nat Commun. 2025 Aug 7;16(1):7268. doi: 10.1038/s41467-025-62378-6.
Polylysogeny, the harboring of multiple prophages within a single bacterial genome, is common among bacterial pathogens and enhances virulence and genome plasticity. Inoviruses (filamentous phages) are often present in multiple copies in major pathogens, leading to polylysogeny. Two highly similar filamentous phages (Pf4 and Pf6) are integrated into the widely distributed model Pseudomonas aeruginosa strain, and both prophages are activated during biofilm formation. It remains unclear whether the two prophages function competitively or cooperatively. Here, we show a crosstalk between Pf4's core region protein RepG4 (PA0717) and Pf6's accessory KKP (kinase-kinase-phosphatase) toxin-antitoxin module that coordinates their propagation. RepG4, involved in Pf4 phage replication, triggers kinase-mediated toxicity of KKP in a dose-dependent manner by degrading the phosphatase antitoxin. This crosstalk serves as a molecular brake, preventing excessive Pf4 production and coordinating the release of both Pf4 and Pf6 phages during biofilm maturation. Our findings provide valuable insights into the significance of the tight regulation between phage core genes and accessory genes in establishing a mutualistic interaction between co-resident prophages.
多溶原性，即单个细菌基因组中存在多个原噬菌体，在细菌病原体中很常见，并增强了毒力和基因组可塑性。丝状噬菌体（丝状噬菌体）在主要病原体中通常以多个拷贝存在，导致多溶原性。两种高度相似的丝状噬菌体（Pf4和Pf6）整合到广泛分布的模式铜绿假单胞菌菌株中，并且在生物膜形成过程中两种原噬菌体均被激活。目前尚不清楚这两种原噬菌体是竞争性还是协同性发挥作用。在这里，我们展示了Pf4的核心区域蛋白RepG4（PA0717）与Pf6的辅助KKP（激酶-激酶-磷酸酶）毒素-抗毒素模块之间的相互作用，该相互作用协调了它们的传播。参与Pf4噬菌体复制的RepG4通过降解磷酸酶抗毒素，以剂量依赖的方式触发KKP的激酶介导的毒性。这种相互作用起到了分子刹车的作用，防止Pf4过度产生，并在生物膜成熟过程中协调Pf4和Pf6噬菌体的释放。我们的研究结果为噬菌体核心基因和辅助基因之间的严格调控在建立共存原噬菌体之间的互利相互作用中的重要性提供了有价值的见解。
