A Dual‐Targeting T6SS DNase Drives Bacterial Antagonism and Eukaryotic Apoptosis via the cGAS‐STING‐TNF Axis
Abstract 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 effecto...
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2025-07-01
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| Online Access: | https://doi.org/10.1002/advs.202504086 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Li Song |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-57974010b866498e99d32c8a8a4033af |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-57974010b866498e99d32c8a8a4033af2025-08-20T02:50:52ZengWileyAdvanced Science2198-38442025-07-011228n/an/a10.1002/advs.202504086A Dual‐Targeting T6SS DNase Drives Bacterial Antagonism and Eukaryotic Apoptosis via the cGAS‐STING‐TNF AxisLi Song0Lei Xu1Pengfei Zhang2Shuying Li3Yichen Qu4Yixin Zhao5Zhenkun Shi6Ruiqi Ma7Yongdong Li8Yi Chen9Yao Wang10Zhengfan Jiang11Gehong Wei12Xihui Shen13Shaanxi Key Laboratory of Agricultural and Environmental Microbiology College of Natural Resources and Environment Northwest A&F University Yangling Shaanxi 12100 P. R. ChinaCollege of Life Sciences Northwest A&F University Yangling Shaanxi 712100 P. R. ChinaCollege of Life Sciences Northwest A&F University Yangling Shaanxi 712100 P. R. ChinaCollege of Life Sciences Northwest A&F University Yangling Shaanxi 712100 P. R. ChinaCollege of Life Sciences Northwest A&F University Yangling Shaanxi 712100 P. R. ChinaCollege of Life Sciences Northwest A&F University Yangling Shaanxi 712100 P. R. ChinaCollege of Life Sciences Northwest A&F University Yangling Shaanxi 712100 P. R. ChinaCollege of Life Sciences Northwest A&F University Yangling Shaanxi 712100 P. R. ChinaNingbo Municipal Center for Disease Control and Prevention Ningbo Zhejiang 315010 P. R. ChinaNingbo Municipal Center for Disease Control and Prevention Ningbo Zhejiang 315010 P. R. ChinaCollege of Life Sciences Northwest A&F University Yangling Shaanxi 712100 P. R. ChinaKey Laboratory of Cell Proliferation and Differentiation of the Ministry of Education School of Life Sciences Peking University Beijing 100871 P. R. ChinaShaanxi Key Laboratory of Agricultural and Environmental Microbiology College of Natural Resources and Environment Northwest A&F University Yangling Shaanxi 12100 P. R. ChinaCollege of Life Sciences Northwest A&F University Yangling Shaanxi 712100 P. R. ChinaAbstract 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.https://doi.org/10.1002/advs.202504086apoptosisDNA damageDNasetrans‐kingdom effectorType VI secretion systems (T6SSs)Yersinia pseudotuberculosis |
| spellingShingle | 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 A Dual‐Targeting T6SS DNase Drives Bacterial Antagonism and Eukaryotic Apoptosis via the cGAS‐STING‐TNF Axis Advanced Science apoptosis DNA damage DNase trans‐kingdom effector Type VI secretion systems (T6SSs) Yersinia pseudotuberculosis |
| title | A Dual‐Targeting T6SS DNase Drives Bacterial Antagonism and Eukaryotic Apoptosis via the cGAS‐STING‐TNF Axis |
| title_full | A Dual‐Targeting T6SS DNase Drives Bacterial Antagonism and Eukaryotic Apoptosis via the cGAS‐STING‐TNF Axis |
| title_fullStr | A Dual‐Targeting T6SS DNase Drives Bacterial Antagonism and Eukaryotic Apoptosis via the cGAS‐STING‐TNF Axis |
| title_full_unstemmed | A Dual‐Targeting T6SS DNase Drives Bacterial Antagonism and Eukaryotic Apoptosis via the cGAS‐STING‐TNF Axis |
| title_short | A Dual‐Targeting T6SS DNase Drives Bacterial Antagonism and Eukaryotic Apoptosis via the cGAS‐STING‐TNF Axis |
| title_sort | dual targeting t6ss dnase drives bacterial antagonism and eukaryotic apoptosis via the cgas sting tnf axis |
| topic | apoptosis DNA damage DNase trans‐kingdom effector Type VI secretion systems (T6SSs) Yersinia pseudotuberculosis |
| url | https://doi.org/10.1002/advs.202504086 |
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