Regulation of interferon alpha production by the MAGUK-family protein CASK under H5N1 infection
CASK, a MAGUK family scaffold protein, regulates gene expression as a transcription co-activator in neurons. However, the mechanism of CASK nucleus translocation and the regulatory function of CASK in myeloid cells remains unclear. Here, we investigated its role in H5N1-infected macrophages. We foun...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1513713/full |
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| author | Jing-Ying Huang Jing-Ying Huang Pei-Shan Sung Shie-Liang Hsieh Shie-Liang Hsieh Shie-Liang Hsieh Shie-Liang Hsieh |
| author_facet | Jing-Ying Huang Jing-Ying Huang Pei-Shan Sung Shie-Liang Hsieh Shie-Liang Hsieh Shie-Liang Hsieh Shie-Liang Hsieh |
| author_sort | Jing-Ying Huang |
| collection | DOAJ |
| description | CASK, a MAGUK family scaffold protein, regulates gene expression as a transcription co-activator in neurons. However, the mechanism of CASK nucleus translocation and the regulatory function of CASK in myeloid cells remains unclear. Here, we investigated its role in H5N1-infected macrophages. We found that H5N1 triggers CASK nuclear translocation via PKR and SRC signaling. HCK, a SRC family kinase, enhances CASK phosphorylation at S395 via CDK5, facilitating CASK’s nuclear entry. Knocking out CASK in myeloid cells specifically reduces interferon-alpha (IFNA) production by hindering the nuclear export of Ifna mRNA, while leaving its mRNA levels unchanged. Myeloid-specific CASK knockout (KO) mice display exacerbated lung inflammation, which correlates with reduced IFNA levels during H5N1 infection. Interactome studies show that H5N1 triggers associations between CASK and CCT4, STIP1, and TNK1. These associations recruit IRF7, POLR2C, TAF15, HNRNPs, and CRM1, enabling the CASK complex to bind to the Ifna promoter, bind co-transcriptionally to Ifna mRNA, and facilitate CRM1-dependent Ifna mRNA export. This underscores CASK’s critical role in the antiviral response. |
| format | Article |
| id | doaj-art-afec8af7f7ce42d1997a82ee04333f6f |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-afec8af7f7ce42d1997a82ee04333f6f2025-01-09T05:10:17ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011510.3389/fimmu.2024.15137131513713Regulation of interferon alpha production by the MAGUK-family protein CASK under H5N1 infectionJing-Ying Huang0Jing-Ying Huang1Pei-Shan Sung2Shie-Liang Hsieh3Shie-Liang Hsieh4Shie-Liang Hsieh5Shie-Liang Hsieh6Doctoral Degree Program of Translational Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, TaiwanImmunology Research Center, National Health Research Institute, Zhunan, TaiwanImmunology Research Center, National Health Research Institute, Zhunan, TaiwanImmunology Research Center, National Health Research Institute, Zhunan, TaiwanInstitute of Clinical Medicine and Institute of Microbiology and Immunology, National Yang Ming Chiao Tung University, Taipei, TaiwanDepartment of Medical Research, Taipei Veterans General Hospital, Taipei, TaiwanMaster Program in Clinical Genomics and Proteomics, School of Pharmacy, Taipei Medical University, Taipei, TaiwanCASK, a MAGUK family scaffold protein, regulates gene expression as a transcription co-activator in neurons. However, the mechanism of CASK nucleus translocation and the regulatory function of CASK in myeloid cells remains unclear. Here, we investigated its role in H5N1-infected macrophages. We found that H5N1 triggers CASK nuclear translocation via PKR and SRC signaling. HCK, a SRC family kinase, enhances CASK phosphorylation at S395 via CDK5, facilitating CASK’s nuclear entry. Knocking out CASK in myeloid cells specifically reduces interferon-alpha (IFNA) production by hindering the nuclear export of Ifna mRNA, while leaving its mRNA levels unchanged. Myeloid-specific CASK knockout (KO) mice display exacerbated lung inflammation, which correlates with reduced IFNA levels during H5N1 infection. Interactome studies show that H5N1 triggers associations between CASK and CCT4, STIP1, and TNK1. These associations recruit IRF7, POLR2C, TAF15, HNRNPs, and CRM1, enabling the CASK complex to bind to the Ifna promoter, bind co-transcriptionally to Ifna mRNA, and facilitate CRM1-dependent Ifna mRNA export. This underscores CASK’s critical role in the antiviral response.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1513713/fullCASKH5N1influenza A virusmacrophagenuclear entryinterferon-alpha |
| spellingShingle | Jing-Ying Huang Jing-Ying Huang Pei-Shan Sung Shie-Liang Hsieh Shie-Liang Hsieh Shie-Liang Hsieh Shie-Liang Hsieh Regulation of interferon alpha production by the MAGUK-family protein CASK under H5N1 infection Frontiers in Immunology CASK H5N1 influenza A virus macrophage nuclear entry interferon-alpha |
| title | Regulation of interferon alpha production by the MAGUK-family protein CASK under H5N1 infection |
| title_full | Regulation of interferon alpha production by the MAGUK-family protein CASK under H5N1 infection |
| title_fullStr | Regulation of interferon alpha production by the MAGUK-family protein CASK under H5N1 infection |
| title_full_unstemmed | Regulation of interferon alpha production by the MAGUK-family protein CASK under H5N1 infection |
| title_short | Regulation of interferon alpha production by the MAGUK-family protein CASK under H5N1 infection |
| title_sort | regulation of interferon alpha production by the maguk family protein cask under h5n1 infection |
| topic | CASK H5N1 influenza A virus macrophage nuclear entry interferon-alpha |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1513713/full |
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