O-GlcNAc transferase plays dual antiviral roles by integrating innate immunity and lipid metabolism
Abstract Viral infection induces robust reprogramming of metabolic pathways in host cells. However, whether host metabolic enzymes detect viral components remains unknown. Our group and others previously identified O-GlcNAc transferase (OGT), an important glucose metabolic enzyme, as a crucial media...
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| Format: | Article |
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-63085-y |
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| author | Hong Dong Chenxi Liang Junjie Zhang Weidong Wu Nitesh Kumar Zihao Liu Yajun Sun Zhiwei Liao Xiaolin Cheng Yanbao Yu Yong Zhang Michael J. Holtzman Jianrong Li Kymberly M. Gowdy Paul G. Thomas Jovica D. Badjic Anjun Ma Qin Ma Jacob S. Yount Shan-Lu Liu Haitao Wen |
| author_facet | Hong Dong Chenxi Liang Junjie Zhang Weidong Wu Nitesh Kumar Zihao Liu Yajun Sun Zhiwei Liao Xiaolin Cheng Yanbao Yu Yong Zhang Michael J. Holtzman Jianrong Li Kymberly M. Gowdy Paul G. Thomas Jovica D. Badjic Anjun Ma Qin Ma Jacob S. Yount Shan-Lu Liu Haitao Wen |
| author_sort | Hong Dong |
| collection | DOAJ |
| description | Abstract Viral infection induces robust reprogramming of metabolic pathways in host cells. However, whether host metabolic enzymes detect viral components remains unknown. Our group and others previously identified O-GlcNAc transferase (OGT), an important glucose metabolic enzyme, as a crucial mediator of the antiviral immune responses. Here, by studying a mouse model with a catalytically impaired OGT, we discover a catalytic activity-independent function of OGT in restraining influenza A virus (IAV) infection in addition to its catalytic activity-dependent effect on MAVS-mediated antiviral immunity. Biochemical studies reveal a critical antiviral effect based on OGT interacting with IAV genomic RNA that requires its N-terminal tetracopeptide repeat-4 motif. This interaction causes the translocation of nuclear OGT to cytosolic lipid droplets (LDs) to destabilize LDs-coating perilipin 2, thereby limiting LDs accumulation and in turn virus replication. In sum, our findings reveal OGT as a multifaceted metabolic sensor that integrates MAVS signaling and lipid metabolism to combat viral infection. |
| format | Article |
| id | doaj-art-7993bdc54c20401daef1468f09ee63f4 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-7993bdc54c20401daef1468f09ee63f42025-08-24T11:37:52ZengNature PortfolioNature Communications2041-17232025-08-0116111910.1038/s41467-025-63085-yO-GlcNAc transferase plays dual antiviral roles by integrating innate immunity and lipid metabolismHong Dong0Chenxi Liang1Junjie Zhang2Weidong Wu3Nitesh Kumar4Zihao Liu5Yajun Sun6Zhiwei Liao7Xiaolin Cheng8Yanbao Yu9Yong Zhang10Michael J. Holtzman11Jianrong Li12Kymberly M. Gowdy13Paul G. Thomas14Jovica D. Badjic15Anjun Ma16Qin Ma17Jacob S. Yount18Shan-Lu Liu19Haitao Wen20Department of Microbial Infection and Immunity, Infectious Disease Institute, The Ohio State UniversityDepartment of Microbial Infection and Immunity, Infectious Disease Institute, The Ohio State UniversityDivision of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State UniversityDepartment of Biomedical Informatics, The Ohio State UniversityDepartment of Chemistry and Biochemistry, The Ohio State UniversityDepartment of Microbial Infection and Immunity, Infectious Disease Institute, The Ohio State UniversityDepartment of Microbial Infection and Immunity, Infectious Disease Institute, The Ohio State UniversityDepartment of Microbial Infection and Immunity, Infectious Disease Institute, The Ohio State UniversityDivision of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State UniversityDepartment of Chemistry and Biochemistry, University of DelawarePulmonary and Critical Care Medicine, Department of Medicine, Washington University School of MedicinePulmonary and Critical Care Medicine, Department of Medicine, Washington University School of MedicineDepartment Veterinary Biosciences, College of Veterinary Medicine, The Ohio State UniversityDivision of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, The Ohio State UniversityDepartment of Host-Microbe Interactions and Department of Immunology, St. Jude Children’s Research HospitalDepartment of Chemistry and Biochemistry, The Ohio State UniversityDepartment of Biomedical Informatics, The Ohio State UniversityDepartment of Biomedical Informatics, The Ohio State UniversityDepartment of Microbial Infection and Immunity, Infectious Disease Institute, The Ohio State UniversityDepartment of Microbial Infection and Immunity, Infectious Disease Institute, The Ohio State UniversityDepartment of Microbial Infection and Immunity, Infectious Disease Institute, The Ohio State UniversityAbstract Viral infection induces robust reprogramming of metabolic pathways in host cells. However, whether host metabolic enzymes detect viral components remains unknown. Our group and others previously identified O-GlcNAc transferase (OGT), an important glucose metabolic enzyme, as a crucial mediator of the antiviral immune responses. Here, by studying a mouse model with a catalytically impaired OGT, we discover a catalytic activity-independent function of OGT in restraining influenza A virus (IAV) infection in addition to its catalytic activity-dependent effect on MAVS-mediated antiviral immunity. Biochemical studies reveal a critical antiviral effect based on OGT interacting with IAV genomic RNA that requires its N-terminal tetracopeptide repeat-4 motif. This interaction causes the translocation of nuclear OGT to cytosolic lipid droplets (LDs) to destabilize LDs-coating perilipin 2, thereby limiting LDs accumulation and in turn virus replication. In sum, our findings reveal OGT as a multifaceted metabolic sensor that integrates MAVS signaling and lipid metabolism to combat viral infection.https://doi.org/10.1038/s41467-025-63085-y |
| spellingShingle | Hong Dong Chenxi Liang Junjie Zhang Weidong Wu Nitesh Kumar Zihao Liu Yajun Sun Zhiwei Liao Xiaolin Cheng Yanbao Yu Yong Zhang Michael J. Holtzman Jianrong Li Kymberly M. Gowdy Paul G. Thomas Jovica D. Badjic Anjun Ma Qin Ma Jacob S. Yount Shan-Lu Liu Haitao Wen O-GlcNAc transferase plays dual antiviral roles by integrating innate immunity and lipid metabolism Nature Communications |
| title | O-GlcNAc transferase plays dual antiviral roles by integrating innate immunity and lipid metabolism |
| title_full | O-GlcNAc transferase plays dual antiviral roles by integrating innate immunity and lipid metabolism |
| title_fullStr | O-GlcNAc transferase plays dual antiviral roles by integrating innate immunity and lipid metabolism |
| title_full_unstemmed | O-GlcNAc transferase plays dual antiviral roles by integrating innate immunity and lipid metabolism |
| title_short | O-GlcNAc transferase plays dual antiviral roles by integrating innate immunity and lipid metabolism |
| title_sort | o glcnac transferase plays dual antiviral roles by integrating innate immunity and lipid metabolism |
| url | https://doi.org/10.1038/s41467-025-63085-y |
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