Dual roles of exostosin glycosyltransferase 1 in Zika virus infection
Many factors involved in heparan sulfate (HS) biosynthesis and metabolism have been reported to play roles in viral infection. However, the detailed mechanisms are still not fully understood. In this study, we report that exostosin glycosyltransferase 1 (EXT1), the HS polymerase, is a critical regul...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2025-12-01
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| Series: | Virulence |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/21505594.2025.2458681 |
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| _version_ | 1849719004014313472 |
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| author | Jiaxin Ling Asifa Khan Matthias Denkewitz Marco Maccarana Åke Lundkvist Jin-Ping Li Jinlin Li |
| author_facet | Jiaxin Ling Asifa Khan Matthias Denkewitz Marco Maccarana Åke Lundkvist Jin-Ping Li Jinlin Li |
| author_sort | Jiaxin Ling |
| collection | DOAJ |
| description | Many factors involved in heparan sulfate (HS) biosynthesis and metabolism have been reported to play roles in viral infection. However, the detailed mechanisms are still not fully understood. In this study, we report that exostosin glycosyltransferase 1 (EXT1), the HS polymerase, is a critical regulatory factor for Zika virus (ZIKV) infection. Knocking out EXT1 dramatically restricts ZIKV infection, which is not due to the inhibition of virus entry resulting from HS deficiency, but mediated by the downregulation of autophagy. Induction of autophagy promotes ZIKV infection, and attenuated autophagy is found in distinct EXT1 knockout (EXT1-KO) cell lines. Induction of autophagy by rapamycin can relieve the ZIKV production defect in EXT1-KO cells. While over-expressing EXT1 results in the reduction of ZIKV production by targeting the viral envelope (E) protein and non-structural protein NS3 in a proteasome-dependent degradation manner. The different roles of EXT1 in ZIKV infection are further confirmed by the data that knocking down EXT1 at the early stage of ZIKV infection represses viral infection, whereas the increase of ZIKV infection is observed when knocking down EXT1 at the late stage of viral infection. This study discovers previously unrecognized intricate roles of EXT1 in ZIKV infection. |
| format | Article |
| id | doaj-art-e42ce05ed3d2422cb9388f8d37271ea6 |
| institution | DOAJ |
| issn | 2150-5594 2150-5608 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Virulence |
| spelling | doaj-art-e42ce05ed3d2422cb9388f8d37271ea62025-08-20T03:12:14ZengTaylor & Francis GroupVirulence2150-55942150-56082025-12-0116110.1080/21505594.2025.2458681Dual roles of exostosin glycosyltransferase 1 in Zika virus infectionJiaxin Ling0Asifa Khan1Matthias Denkewitz2Marco Maccarana3Åke Lundkvist4Jin-Ping Li5Jinlin Li6Department of Medical Biochemistry and Microbiology, The Biomedical Center, Uppsala University, Uppsala, SwedenDepartment of Medical Biochemistry and Microbiology, The Biomedical Center, Uppsala University, Uppsala, SwedenDepartment of Medical Biochemistry and Microbiology, The Biomedical Center, Uppsala University, Uppsala, SwedenDepartment of Medical Biochemistry and Microbiology, The Biomedical Center, Uppsala University, Uppsala, SwedenDepartment of Medical Biochemistry and Microbiology, The Biomedical Center, Uppsala University, Uppsala, SwedenDepartment of Medical Biochemistry and Microbiology, The Biomedical Center, Uppsala University, Uppsala, SwedenDepartment of Medical Biochemistry and Microbiology, The Biomedical Center, Uppsala University, Uppsala, SwedenMany factors involved in heparan sulfate (HS) biosynthesis and metabolism have been reported to play roles in viral infection. However, the detailed mechanisms are still not fully understood. In this study, we report that exostosin glycosyltransferase 1 (EXT1), the HS polymerase, is a critical regulatory factor for Zika virus (ZIKV) infection. Knocking out EXT1 dramatically restricts ZIKV infection, which is not due to the inhibition of virus entry resulting from HS deficiency, but mediated by the downregulation of autophagy. Induction of autophagy promotes ZIKV infection, and attenuated autophagy is found in distinct EXT1 knockout (EXT1-KO) cell lines. Induction of autophagy by rapamycin can relieve the ZIKV production defect in EXT1-KO cells. While over-expressing EXT1 results in the reduction of ZIKV production by targeting the viral envelope (E) protein and non-structural protein NS3 in a proteasome-dependent degradation manner. The different roles of EXT1 in ZIKV infection are further confirmed by the data that knocking down EXT1 at the early stage of ZIKV infection represses viral infection, whereas the increase of ZIKV infection is observed when knocking down EXT1 at the late stage of viral infection. This study discovers previously unrecognized intricate roles of EXT1 in ZIKV infection.https://www.tandfonline.com/doi/10.1080/21505594.2025.2458681ZIKVEXT1heparan sulfateautophagy |
| spellingShingle | Jiaxin Ling Asifa Khan Matthias Denkewitz Marco Maccarana Åke Lundkvist Jin-Ping Li Jinlin Li Dual roles of exostosin glycosyltransferase 1 in Zika virus infection Virulence ZIKV EXT1 heparan sulfate autophagy |
| title | Dual roles of exostosin glycosyltransferase 1 in Zika virus infection |
| title_full | Dual roles of exostosin glycosyltransferase 1 in Zika virus infection |
| title_fullStr | Dual roles of exostosin glycosyltransferase 1 in Zika virus infection |
| title_full_unstemmed | Dual roles of exostosin glycosyltransferase 1 in Zika virus infection |
| title_short | Dual roles of exostosin glycosyltransferase 1 in Zika virus infection |
| title_sort | dual roles of exostosin glycosyltransferase 1 in zika virus infection |
| topic | ZIKV EXT1 heparan sulfate autophagy |
| url | https://www.tandfonline.com/doi/10.1080/21505594.2025.2458681 |
| work_keys_str_mv | AT jiaxinling dualrolesofexostosinglycosyltransferase1inzikavirusinfection AT asifakhan dualrolesofexostosinglycosyltransferase1inzikavirusinfection AT matthiasdenkewitz dualrolesofexostosinglycosyltransferase1inzikavirusinfection AT marcomaccarana dualrolesofexostosinglycosyltransferase1inzikavirusinfection AT akelundkvist dualrolesofexostosinglycosyltransferase1inzikavirusinfection AT jinpingli dualrolesofexostosinglycosyltransferase1inzikavirusinfection AT jinlinli dualrolesofexostosinglycosyltransferase1inzikavirusinfection |