USP5 inhibits anti-RNA viral innate immunity by deconjugating K48-linked unanchored and K63-linked anchored ubiquitin on IRF3.
Interferon regulatory factor 3 (IRF3) is a central hub transcription factor that controls host antiviral innate immunity. The expression and function of IRF3 are tightly regulated by the post-translational modifications. However, it is unknown whether unanchored ubiquitination and deubiquitination o...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2025-01-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1012843 |
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| author | Zigang Qiao Dapei Li Fan Zhang Jingfei Zhu Siying Liu Xue Bai Haiping Yao Zhengrong Chen Yongdong Yan Xiulong Xu Feng Ma |
| author_facet | Zigang Qiao Dapei Li Fan Zhang Jingfei Zhu Siying Liu Xue Bai Haiping Yao Zhengrong Chen Yongdong Yan Xiulong Xu Feng Ma |
| author_sort | Zigang Qiao |
| collection | DOAJ |
| description | Interferon regulatory factor 3 (IRF3) is a central hub transcription factor that controls host antiviral innate immunity. The expression and function of IRF3 are tightly regulated by the post-translational modifications. However, it is unknown whether unanchored ubiquitination and deubiquitination of IRF3 involve modulating antiviral innate immunity against RNA viruses. Here, we find that USP5, a deubiquitinase (DUB) regulating unanchored polyubiquitin, is downregulated during host anti-RNA viral innate immunity in a type I interferon (IFN-I) receptor (IFNAR)-dependent manner. USP5 is further identified to inhibit IRF3-triggered antiviral immune responses through its DUB enzyme activity. K48-linked unanchored ubiquitin promotes IRF3-driven transcription of IFN-β and induction of IFN-stimulated genes (ISGs) in a dose-dependent manner. USP5 simultaneously removes both K48-linked unanchored and K63-linked anchored polyubiquitin chains on IRF3. Our study not only provides evidence that unanchored ubiquitin regulates anti-RNA viral innate immunity but also proposes a novel mechanism for DUB-controlled IRF3 activation, suggesting that USP5 is a potential target for the treatment of RNA viral infectious diseases. |
| format | Article |
| id | doaj-art-5483d9e78e6340cea32f2600a3f07eda |
| institution | OA Journals |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-5483d9e78e6340cea32f2600a3f07eda2025-08-20T02:20:33ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742025-01-01211e101284310.1371/journal.ppat.1012843USP5 inhibits anti-RNA viral innate immunity by deconjugating K48-linked unanchored and K63-linked anchored ubiquitin on IRF3.Zigang QiaoDapei LiFan ZhangJingfei ZhuSiying LiuXue BaiHaiping YaoZhengrong ChenYongdong YanXiulong XuFeng MaInterferon regulatory factor 3 (IRF3) is a central hub transcription factor that controls host antiviral innate immunity. The expression and function of IRF3 are tightly regulated by the post-translational modifications. However, it is unknown whether unanchored ubiquitination and deubiquitination of IRF3 involve modulating antiviral innate immunity against RNA viruses. Here, we find that USP5, a deubiquitinase (DUB) regulating unanchored polyubiquitin, is downregulated during host anti-RNA viral innate immunity in a type I interferon (IFN-I) receptor (IFNAR)-dependent manner. USP5 is further identified to inhibit IRF3-triggered antiviral immune responses through its DUB enzyme activity. K48-linked unanchored ubiquitin promotes IRF3-driven transcription of IFN-β and induction of IFN-stimulated genes (ISGs) in a dose-dependent manner. USP5 simultaneously removes both K48-linked unanchored and K63-linked anchored polyubiquitin chains on IRF3. Our study not only provides evidence that unanchored ubiquitin regulates anti-RNA viral innate immunity but also proposes a novel mechanism for DUB-controlled IRF3 activation, suggesting that USP5 is a potential target for the treatment of RNA viral infectious diseases.https://doi.org/10.1371/journal.ppat.1012843 |
| spellingShingle | Zigang Qiao Dapei Li Fan Zhang Jingfei Zhu Siying Liu Xue Bai Haiping Yao Zhengrong Chen Yongdong Yan Xiulong Xu Feng Ma USP5 inhibits anti-RNA viral innate immunity by deconjugating K48-linked unanchored and K63-linked anchored ubiquitin on IRF3. PLoS Pathogens |
| title | USP5 inhibits anti-RNA viral innate immunity by deconjugating K48-linked unanchored and K63-linked anchored ubiquitin on IRF3. |
| title_full | USP5 inhibits anti-RNA viral innate immunity by deconjugating K48-linked unanchored and K63-linked anchored ubiquitin on IRF3. |
| title_fullStr | USP5 inhibits anti-RNA viral innate immunity by deconjugating K48-linked unanchored and K63-linked anchored ubiquitin on IRF3. |
| title_full_unstemmed | USP5 inhibits anti-RNA viral innate immunity by deconjugating K48-linked unanchored and K63-linked anchored ubiquitin on IRF3. |
| title_short | USP5 inhibits anti-RNA viral innate immunity by deconjugating K48-linked unanchored and K63-linked anchored ubiquitin on IRF3. |
| title_sort | usp5 inhibits anti rna viral innate immunity by deconjugating k48 linked unanchored and k63 linked anchored ubiquitin on irf3 |
| url | https://doi.org/10.1371/journal.ppat.1012843 |
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