Journal
IMMUNOLOGY
Volume 163, Issue 3, Pages 278-292Publisher
WILEY
DOI: 10.1111/imm.13315
Keywords
antiviral response; innate immunity; interferon; IRF3; MID1; ubiquitination
Categories
Funding
- National Key R&D Program of China [(2018YFC1705500): 2018YFC1705505]
- National Natural Science Foundation of China [31770177, 31970846]
- University Natural Science Foundation of Jiangsu Province [18KJA180010]
- Medical Health Science and Technology Project of Zhejiang Provincial Health Commission [2020KY368]
- Gusu Medical Talent
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
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Midline-1 (MID1) is identified as a ubiquitin E3 ligase of IRF3, which downregulates IRF3 protein levels and restricts IFN-I production, thus limiting cellular antiviral response.
Interferon regulatory factor 3 (IRF3) is a critical transcription factor for inducing production of type I interferons (IFN-I) and regulating host antiviral response. Although IRF3 activation during viral infection has been extensively studied, the inhibitory regulation of IRF3 remains largely unexplored. Here, we revealed that Midline-1 (MID1) is a ubiquitin E3 ligase of IRF3 that plays essential roles in regulating the production of IFN-I. We found that MID1 physically interacts with IRF3 and downregulates IRF3 protein levels. Next, we demonstrated that MID1 can induce K48-linked polyubiquitination of IRF3, thus lowing the protein stability of IRF3. Our further studies identified Lys313 as a major ubiquitin acceptor lysine of IRF3 induced by MID1. Finally, MID1-mediated ubiquitination and degradation of IRF3 restrict IFN-I production and cellular antiviral response. This study uncovers a role of MID1 in regulating innate antiviral immunity and may provide a potential target for enhancing host antiviral activity.
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