论文题目：A Dual-Targeting T6SS DNase Drives Bacterial Antagonism and Eukaryotic Apoptosis via the cGAS-STING-TNF Axis
论文作者：Li Song#, Lei Xu#, Pengfei Zhang, Shuying Li, Yichen Qu, Yixin Zhao, Zhenkun Shi, Ruiqi Ma, Yongdong Li, Yi Chen, Yao Wang, Zhengfan Jiang, Gehong Wei*, Xihui Shen*
论文摘要：The Type VI secretion system (T6SS) is a key virulence mechanism utilized by many Gram-negative bacteria to mediate the microbial competition and host pathogenesis. Despite the identification of diverse T6SS effectors targeting eukaryotic or prokaryotic cells, the trans-kingdom T6SS effectors that simultaneously target both eukaryotic and prokaryotic cells remain rarely reported. In this study, it is demonstrated that Yersinia pseudotuberculosis (Yptb) T6SS secretes a DNase effector, TkeA, which induces apoptosis in host cells. The translocation of TkeA into host cells causes nuclear DNA damage. This, in turn, activates the DNA-sensing cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway. The activation of the cGAS-STING pathway by TkeA subsequently triggers apoptosis in host cells via extrinsic pathways, with tumor necrosis factor (TNF) signaling playing a critical role. Additionally, TkeA enhances bacterial competition by targeting rival bacteria, thereby promoting host colonization. These findings reveal that the transkingdom T6SS effector TkeA executes a "one weapon, two battlefields" strategy, acting as a trans-kingdom effector that enhances interbacterial competition while inducing apoptosis in host cells through the activation of the cGAS-STING-TNF axis. This highlights a previously unrecognized dimension of bacterial virulence strategies and expands the understanding of host-pathogen interactions involving T6SS effectors.
细菌VI型分泌系统（T6SS）是革兰氏阴性细菌用来介导微生物竞争和宿主致病性的重要武器。尽管当前已鉴定到多种T6SS能够分别靶向真核细胞或原核细胞的效应蛋白，但同时靶向真核细胞和原核细胞的跨界型T6SS效应蛋白仍鲜有报道。在本研究中，发现假结合耶尔森氏菌（ Yersinia pseudotuberculosis ， Yptb ）的T6SS分泌的DNase效应蛋白TkeA能够诱导宿主细胞凋亡。TkeA通过T6SS转运进入真核细胞后，能够诱导核DNA损伤，并激活DNA感知通路中的环状GMP-AMP合成酶（cGAS）/干扰素基因刺激因子（STING）通路。TkeA激活cGAS-STING通路后，通过外源性途径触发宿主细胞凋亡，其中肿瘤坏死因子（TNF）信号在这一过程中起到了关键作用。此外，TkeA通过靶向竞争细菌，增强了细菌之间的竞争力。这种双重作用最终促进假结合耶尔森氏菌在宿主中的定殖。这些结果揭示了跨界型T6SS效应蛋白TkeA在细菌竞争与宿主细胞凋亡中发挥的双重作用，体现了“一石二鸟”策略，既介导了细菌间的杀菌竞争，又通过激活cGAS-STING-TNF信号通路诱导宿主细胞凋亡。这一发现为细菌毒力策略提供了新的视角，并拓宽了对T6SS效应蛋白在宿主-病原菌相互作用中的作用的理解。
文章链接：https://advanced.onlinelibrary.wiley.com/doi/10.1002/advs.202504086