Abstract
Accumulating evidence has shown that long noncoding RNAs (lncRNAs) are involved in several biological processes, including immune responses. However, the role of lncRNAs in antiviral innate immune responses remains largely elusive. Here, we identify an uncharacterized human lncRNA AVAN from influenza A virus (IAV) infected patients, that is significantly upregulated following RNA virus infection. During IAV infection, AVAN play an indispensable role in antiviral immune responses. In vivo, we enforced the expression of AVAN in transgenic mice or adeno-associated virus encoding AVAN delivery system and found that AVAN significantly alleviated IAV virulence and virus replication. Mechanistically, nuclear AVAN positively regulates the transcription of forkhead box O3A (FOXO3a) by associating with its promoter and inducing chromatin remodeling to promote neutrophil chemotaxis. Meanwhile, cytoplasmic AVAN binds directly to the E3 ligase TRIM25 and enhances TRIM25-mediated K63-linked ubiquitination of RIG-I, thereby promoting TRIM25- and RIG-I-mediated antiviral innate immune responses, including the induction of type I interferon and ISGs. Moreover, AVAN binds to the B Box/CCD domain of TRIM25 and 1–200nt of AVAN were the functional moieties. Collectively, our findings highlight the potential clinical implications of human lncRNA AVAN as a key positive regulator of the antiviral innate immune response and a promising target for developing broad antiviral therapeutics.
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Acknowledgements
We thank Dr. Pin Wang (Navy Medical University) and Dr. Qiang Wang (Harvard Medical School) for providing plasmids for this research. We are grateful to Prof. Bing Ni (Army Medical University) for insightful discussions and helpful comments on the article. We thank Dr. Hongjing Gu (Beijing Institute of Microbiology and Epidemiology), Dr. Zhongpeng Zhao (Beijing Institute of Microbiology and Epidemiology), Fang Sun (Fifth Medical Center of Chinese PLA General Hospital), and Jinxia Cheng (Fifth Medical Center of Chinese PLA General Hospital) for their help in this research.
Funding
This work was supported in part by funding from the National Programs for High Technology Research and Development of China (SS2015AA020924), the National Major Research and Development Program of China (No. 2017YFC1200800), and the Natural Science Foundation of China (81771700).
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Authors LL, PY, RC, and XW conceived and designed the experiments; CL, LL, QL, SC, KW, LNZ, and MX performed the experiments; YD, CW, LLZ, ZL, and JL analyzed the data; and CL, LL, KW, and QL wrote the manuscript.
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All experimental procedures in mice were approved by the Institutional 609 Animal Care and Use Committee of the Academy of Military Medical Sciences. This study 610 was approved by the Ethics Committee of the Chinese PLA General Hospital
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Lai, C., Liu, L., Liu, Q. et al. Long noncoding RNA AVAN promotes antiviral innate immunity by interacting with TRIM25 and enhancing the transcription of FOXO3a. Cell Death Differ 28, 2900–2915 (2021). https://doi.org/10.1038/s41418-021-00791-2
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DOI: https://doi.org/10.1038/s41418-021-00791-2
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