LINC2781 enhances antiviral immunity against coxsackievirus B5 infection by activating the JAK-STAT pathway and blocking G3BP2-mediated STAT1 degradation
ABSTRACT Coxsackievirus B5 (CVB5) is a primary causative agent of hand, foot, and mouth disease (HFMD), and some cases are also associated with severe complications through invasion of the central nervous system, resulting in death. Currently, there are no specific antiviral drugs or effective vacci...
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American Society for Microbiology
2025-07-01
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| Series: | mSphere |
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| Online Access: | https://journals.asm.org/doi/10.1128/msphere.00062-25 |
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| author | Jiayu Zhang Jing Li Yonghan Luo Timothy J. Mahony Jingru Gao Yanchun Wang Xiaotao Yang Fan Yang Xia Ou Jihong Zhang Heng Yang Wei Chen |
| author_facet | Jiayu Zhang Jing Li Yonghan Luo Timothy J. Mahony Jingru Gao Yanchun Wang Xiaotao Yang Fan Yang Xia Ou Jihong Zhang Heng Yang Wei Chen |
| author_sort | Jiayu Zhang |
| collection | DOAJ |
| description | ABSTRACT Coxsackievirus B5 (CVB5) is a primary causative agent of hand, foot, and mouth disease (HFMD), and some cases are also associated with severe complications through invasion of the central nervous system, resulting in death. Currently, there are no specific antiviral drugs or effective vaccines available for CVB5. Long non-coding RNAs (lncRNAs) have been shown to play significant roles in various diseases. In our research, we identified a novel lncRNA, LINC2781, which is significantly upregulated during CVB5 infection of SH-SY5Y cells. Characteristic analysis showed that LINC2781 is mainly located in the cytoplasm of infected cells, with significantly higher expression in the intestines and the spleen of CVB5-infected mice. Functional studies revealed that LINC2781 activates the JAK-STAT pathway via STAT1, promoting the expression of interferon-stimulated genes (ISGs) and inhibiting CVB5 replication. Mechanistically, LINC2781 directly binds to GTPase-activating protein SH3 domain-binding protein 2 (G3BP2), preventing G3BP2-mediated degradation of STAT1 through ubiquitination. In vivo, LINC2781 was shown to reduce the susceptibility of BALB/c mice to viral infection and alleviate viral-induced damage in both the intestines and the spleen. Clinical samples further confirmed a strong correlation between the expression of LINC2781 and CVB5 infection. Our findings demonstrate that CVB5-induced LINC2781 enhances STAT1 activation by blocking the suppressive effects of G3BP2 on immune responses, providing a potential foundation for developing antiviral therapies targeting the lncRNA.IMPORTANCEWe investigate the role of lncRNA in virus-host interactions and identify a novel cytoplasmic lncRNA, LINC2781, whose expression is upregulated following CVB5 infection. LINC2781 specifically binds to G3BP2, preventing G3BP2 from degrading STAT1, thereby activating the JAK-STAT pathway, promoting the expression of ISGs, and ultimately inhibiting viral replication. Meanwhile, a strong correlation exists between the expression of LINC2781 and CVB5 infection in cells and clinical samples. |
| format | Article |
| id | doaj-art-23cb0d2b92ad4cfd81922b81a97c94d8 |
| institution | DOAJ |
| issn | 2379-5042 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mSphere |
| spelling | doaj-art-23cb0d2b92ad4cfd81922b81a97c94d82025-08-20T02:46:00ZengAmerican Society for MicrobiologymSphere2379-50422025-07-0110710.1128/msphere.00062-25LINC2781 enhances antiviral immunity against coxsackievirus B5 infection by activating the JAK-STAT pathway and blocking G3BP2-mediated STAT1 degradationJiayu Zhang0Jing Li1Yonghan Luo2Timothy J. Mahony3Jingru Gao4Yanchun Wang5Xiaotao Yang6Fan Yang7Xia Ou8Jihong Zhang9Heng Yang10Wei Chen11Medical School, Kunming University of Science and Technology, Kunming, Yunnan Province, ChinaMedical School, Kunming University of Science and Technology, Kunming, Yunnan Province, ChinaSecond Department of Infectious Disease, Kunming Children’s Hospital, Kunming, Yunnan, ChinaQueensland Alliance for Agriculture and Food Innovation, The University of Queensland, Brisbane, AustraliaMedical School, Kunming University of Science and Technology, Kunming, Yunnan Province, ChinaSecond Department of Infectious Disease, Kunming Children’s Hospital, Kunming, Yunnan, ChinaSecond Department of Infectious Disease, Kunming Children’s Hospital, Kunming, Yunnan, ChinaMedical School, Kunming University of Science and Technology, Kunming, Yunnan Province, ChinaMedical School, Kunming University of Science and Technology, Kunming, Yunnan Province, ChinaMedical School, Kunming University of Science and Technology, Kunming, Yunnan Province, ChinaCollege of Agriculture and Life Sciences, Kunming University, Kunming, Yunnan Province, ChinaMedical School, Kunming University of Science and Technology, Kunming, Yunnan Province, ChinaABSTRACT Coxsackievirus B5 (CVB5) is a primary causative agent of hand, foot, and mouth disease (HFMD), and some cases are also associated with severe complications through invasion of the central nervous system, resulting in death. Currently, there are no specific antiviral drugs or effective vaccines available for CVB5. Long non-coding RNAs (lncRNAs) have been shown to play significant roles in various diseases. In our research, we identified a novel lncRNA, LINC2781, which is significantly upregulated during CVB5 infection of SH-SY5Y cells. Characteristic analysis showed that LINC2781 is mainly located in the cytoplasm of infected cells, with significantly higher expression in the intestines and the spleen of CVB5-infected mice. Functional studies revealed that LINC2781 activates the JAK-STAT pathway via STAT1, promoting the expression of interferon-stimulated genes (ISGs) and inhibiting CVB5 replication. Mechanistically, LINC2781 directly binds to GTPase-activating protein SH3 domain-binding protein 2 (G3BP2), preventing G3BP2-mediated degradation of STAT1 through ubiquitination. In vivo, LINC2781 was shown to reduce the susceptibility of BALB/c mice to viral infection and alleviate viral-induced damage in both the intestines and the spleen. Clinical samples further confirmed a strong correlation between the expression of LINC2781 and CVB5 infection. Our findings demonstrate that CVB5-induced LINC2781 enhances STAT1 activation by blocking the suppressive effects of G3BP2 on immune responses, providing a potential foundation for developing antiviral therapies targeting the lncRNA.IMPORTANCEWe investigate the role of lncRNA in virus-host interactions and identify a novel cytoplasmic lncRNA, LINC2781, whose expression is upregulated following CVB5 infection. LINC2781 specifically binds to G3BP2, preventing G3BP2 from degrading STAT1, thereby activating the JAK-STAT pathway, promoting the expression of ISGs, and ultimately inhibiting viral replication. Meanwhile, a strong correlation exists between the expression of LINC2781 and CVB5 infection in cells and clinical samples.https://journals.asm.org/doi/10.1128/msphere.00062-25coxsackievirus B5 (CVB5)long non-coding RNAs (lncRNAs)LINC2781; GTPase-activating protein SH3 domain-binding protein 2 (G3BP2)STAT1 |
| spellingShingle | Jiayu Zhang Jing Li Yonghan Luo Timothy J. Mahony Jingru Gao Yanchun Wang Xiaotao Yang Fan Yang Xia Ou Jihong Zhang Heng Yang Wei Chen LINC2781 enhances antiviral immunity against coxsackievirus B5 infection by activating the JAK-STAT pathway and blocking G3BP2-mediated STAT1 degradation mSphere coxsackievirus B5 (CVB5) long non-coding RNAs (lncRNAs) LINC2781; GTPase-activating protein SH3 domain-binding protein 2 (G3BP2) STAT1 |
| title | LINC2781 enhances antiviral immunity against coxsackievirus B5 infection by activating the JAK-STAT pathway and blocking G3BP2-mediated STAT1 degradation |
| title_full | LINC2781 enhances antiviral immunity against coxsackievirus B5 infection by activating the JAK-STAT pathway and blocking G3BP2-mediated STAT1 degradation |
| title_fullStr | LINC2781 enhances antiviral immunity against coxsackievirus B5 infection by activating the JAK-STAT pathway and blocking G3BP2-mediated STAT1 degradation |
| title_full_unstemmed | LINC2781 enhances antiviral immunity against coxsackievirus B5 infection by activating the JAK-STAT pathway and blocking G3BP2-mediated STAT1 degradation |
| title_short | LINC2781 enhances antiviral immunity against coxsackievirus B5 infection by activating the JAK-STAT pathway and blocking G3BP2-mediated STAT1 degradation |
| title_sort | linc2781 enhances antiviral immunity against coxsackievirus b5 infection by activating the jak stat pathway and blocking g3bp2 mediated stat1 degradation |
| topic | coxsackievirus B5 (CVB5) long non-coding RNAs (lncRNAs) LINC2781; GTPase-activating protein SH3 domain-binding protein 2 (G3BP2) STAT1 |
| url | https://journals.asm.org/doi/10.1128/msphere.00062-25 |
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