DENV-2 NS1 promotes AMPK-LKB1 interaction to activate AMPK/ERK/mTOR signaling pathway to induce autophagy
Abstract The global incidence of dengue fever has gradually increased in recent years, posing a serious threat to human health. In the absence of specific anti-dengue drugs, understanding the interaction of Dengue virus (DENV) with the host is essential for the development of effective therapeutic m...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-10-01
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| Series: | Virology Journal |
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| Online Access: | https://doi.org/10.1186/s12985-023-02166-0 |
| _version_ | 1797578162559778816 |
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| author | Ning Wu Jinzhong Ji Xiaoqin Gou Pan Hu Yao Cheng Yuhang Liu Yuanying Wang Qilong Zhang Li Zuo |
| author_facet | Ning Wu Jinzhong Ji Xiaoqin Gou Pan Hu Yao Cheng Yuhang Liu Yuanying Wang Qilong Zhang Li Zuo |
| author_sort | Ning Wu |
| collection | DOAJ |
| description | Abstract The global incidence of dengue fever has gradually increased in recent years, posing a serious threat to human health. In the absence of specific anti-dengue drugs, understanding the interaction of Dengue virus (DENV) with the host is essential for the development of effective therapeutic measures. Autophagy is often activated during DENV infection to promote viral replication, but the mechanism of how DENV's own proteins induce autophagy has not been clarified. In this study, we first preliminarily identified DENV-2 NS1 as the most likely viral protein for DENV-2-induced autophagy with the help of molecular docking techniques. Further experimental results confirmed that DENV-2 NS1 regulates DENV-2 infection of HUVEC-induced autophagy through the AMPK/ERK/mTOR signaling pathway. Mechanistically, DENV-2 NS1 mainly interacted with AMPK by means of its Wing structural domain, and NS1 bound to all three structural domains on the AMPKα subunit. Finally, the experimental results showed that DENV-2 NS1 promoted the interaction between LKB1 and AMPKα1 and thus activated AMPK by both increasing the expression of LKB1 and binding LKB1. In conclusion, the results of this study revealed that DENV-2 NS1 protein served as a platform for the interaction between AMPK and LKB1 after DENV-2 infection with HUVEC, and pulled AMPK and LKB1 together to form a complex. LKB1 to form a complex, promoting LKB1 action on the kinase structural domain of AMPKα1, which in turn promotes phosphorylation of the Thr172 site on the AMPK kinase structural domain and activates AMPK, thereby positively regulating the AMPK/ERK/mTOR signaling pathway and inducing autophagy. The present discovery improves our understanding of DENV-2-induced host autophagy and contributes to the development of anti-dengue drugs. |
| first_indexed | 2024-03-10T22:18:15Z |
| format | Article |
| id | doaj.art-477e5d055e5a41d1b52ea43c510077b3 |
| institution | Directory Open Access Journal |
| issn | 1743-422X |
| language | English |
| last_indexed | 2024-03-10T22:18:15Z |
| publishDate | 2023-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Virology Journal |
| spelling | doaj.art-477e5d055e5a41d1b52ea43c510077b32023-11-19T12:21:44ZengBMCVirology Journal1743-422X2023-10-0120111310.1186/s12985-023-02166-0DENV-2 NS1 promotes AMPK-LKB1 interaction to activate AMPK/ERK/mTOR signaling pathway to induce autophagyNing Wu0Jinzhong Ji1Xiaoqin Gou2Pan Hu3Yao Cheng4Yuhang Liu5Yuanying Wang6Qilong Zhang7Li Zuo8Chemistry and Biochemistry Laboratory, Guizhou Medical UniversityChemistry and Biochemistry Laboratory, Guizhou Medical UniversityChemistry and Biochemistry Laboratory, Guizhou Medical UniversityChemistry and Biochemistry Laboratory, Guizhou Medical UniversityChemistry and Biochemistry Laboratory, Guizhou Medical UniversityChemistry and Biochemistry Laboratory, Guizhou Medical UniversityChemistry and Biochemistry Laboratory, Guizhou Medical UniversityChemistry and Biochemistry Laboratory, Guizhou Medical UniversityDepartment of Immunology, Guizhou Medical UniversityAbstract The global incidence of dengue fever has gradually increased in recent years, posing a serious threat to human health. In the absence of specific anti-dengue drugs, understanding the interaction of Dengue virus (DENV) with the host is essential for the development of effective therapeutic measures. Autophagy is often activated during DENV infection to promote viral replication, but the mechanism of how DENV's own proteins induce autophagy has not been clarified. In this study, we first preliminarily identified DENV-2 NS1 as the most likely viral protein for DENV-2-induced autophagy with the help of molecular docking techniques. Further experimental results confirmed that DENV-2 NS1 regulates DENV-2 infection of HUVEC-induced autophagy through the AMPK/ERK/mTOR signaling pathway. Mechanistically, DENV-2 NS1 mainly interacted with AMPK by means of its Wing structural domain, and NS1 bound to all three structural domains on the AMPKα subunit. Finally, the experimental results showed that DENV-2 NS1 promoted the interaction between LKB1 and AMPKα1 and thus activated AMPK by both increasing the expression of LKB1 and binding LKB1. In conclusion, the results of this study revealed that DENV-2 NS1 protein served as a platform for the interaction between AMPK and LKB1 after DENV-2 infection with HUVEC, and pulled AMPK and LKB1 together to form a complex. LKB1 to form a complex, promoting LKB1 action on the kinase structural domain of AMPKα1, which in turn promotes phosphorylation of the Thr172 site on the AMPK kinase structural domain and activates AMPK, thereby positively regulating the AMPK/ERK/mTOR signaling pathway and inducing autophagy. The present discovery improves our understanding of DENV-2-induced host autophagy and contributes to the development of anti-dengue drugs.https://doi.org/10.1186/s12985-023-02166-0DENV-2AutophagyDENV-2 NS1AMPKLKB1AMPK/ERK/mTOR signaling pathway |
| spellingShingle | Ning Wu Jinzhong Ji Xiaoqin Gou Pan Hu Yao Cheng Yuhang Liu Yuanying Wang Qilong Zhang Li Zuo DENV-2 NS1 promotes AMPK-LKB1 interaction to activate AMPK/ERK/mTOR signaling pathway to induce autophagy Virology Journal DENV-2 Autophagy DENV-2 NS1 AMPK LKB1 AMPK/ERK/mTOR signaling pathway |
| title | DENV-2 NS1 promotes AMPK-LKB1 interaction to activate AMPK/ERK/mTOR signaling pathway to induce autophagy |
| title_full | DENV-2 NS1 promotes AMPK-LKB1 interaction to activate AMPK/ERK/mTOR signaling pathway to induce autophagy |
| title_fullStr | DENV-2 NS1 promotes AMPK-LKB1 interaction to activate AMPK/ERK/mTOR signaling pathway to induce autophagy |
| title_full_unstemmed | DENV-2 NS1 promotes AMPK-LKB1 interaction to activate AMPK/ERK/mTOR signaling pathway to induce autophagy |
| title_short | DENV-2 NS1 promotes AMPK-LKB1 interaction to activate AMPK/ERK/mTOR signaling pathway to induce autophagy |
| title_sort | denv 2 ns1 promotes ampk lkb1 interaction to activate ampk erk mtor signaling pathway to induce autophagy |
| topic | DENV-2 Autophagy DENV-2 NS1 AMPK LKB1 AMPK/ERK/mTOR signaling pathway |
| url | https://doi.org/10.1186/s12985-023-02166-0 |
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