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An Alternative Splicing of Tupaia STING Modulated Anti-RNA Virus Responses by Targeting MDA5-LGP2 and IRF3

Ling Xu, Dandan Yu, Li Peng, Yong Wu, Yu Fan, Tianle Gu, Yu-Lin Yao, Jin Zhong, Xinwen Chen and Yong-Gang Yao
J Immunol May 6, 2020, ji1901320; DOI: https://doi.org/10.4049/jimmunol.1901320
Ling Xu
*Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China;
†Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan 650223, China;
‡Kunming Primate Research Center of the Chinese Academy of Sciences, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, China;
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Dandan Yu
*Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China;
†Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan 650223, China;
‡Kunming Primate Research Center of the Chinese Academy of Sciences, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, China;
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Li Peng
*Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China;
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Yong Wu
*Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China;
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Yu Fan
*Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China;
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Tianle Gu
*Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China;
§Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China;
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Yu-Lin Yao
*Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China;
§Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China;
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Jin Zhong
¶Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China;
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Xinwen Chen
‖State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; and
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Yong-Gang Yao
*Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China;
†Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan 650223, China;
‡Kunming Primate Research Center of the Chinese Academy of Sciences, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, China;
§Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China;
#Kunming Institute of Zoology–Chinese University of Hong Kong Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
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Key Points

  • Tupaia STING has two alternative splicing isoforms, tSTING-FL and tSTING-mini.

  • tSTING-mini is critical for RNA virus-induced antiviral signaling transduction.

  • tSTING-mini enhances MDA5–LGP2-mediated antiviral response and IRF3 phosphorylation.

Abstract

The stimulator of IFN genes (STING; also known as MITA, TMEM173, MPYS, or ERIS) is generally regarded as a key adaptor protein for sensing pathogenic DNA genomes. However, its role in RNA viral signaling as part of the innate immunity system remains controversial. In this study, we identified two isoforms of STING (a full-length Tupaia STING [tSTING-FL] and a Tupaia STING short isoform [tSTING-mini]) in the Chinese tree shrew (Tupaia belangeri chinensis), a close relative of primates. tSTING-FL played a key role in the HSV-1–triggered type I IFN signaling pathway, whereas tSTING-mini was critical for RNA virus-induced antiviral signaling transduction. tSTING-mini, but not tSTING-FL, interacted with tMDA5–tLGP2 and tIRF3 in resting cells. Upon RNA virus infection, tSTING-mini caused a rapid enhancement of the tMDA5–tLGP2-mediated antiviral response and acted earlier than tSTING-FL. Furthermore, tSTING-mini was translocated from the cytoplasm to the nucleus during RNA virus infection and promoted tIRF3 phosphorylation through tSTING-mini–tIRF3 interaction, leading to a restriction of viral replication. After the initiation of antiviral effect, tSTING-mini underwent rapid degradation by tDTX3L–tPAPR9 via k48-linked ubiquitination through a proteasome-dependent pathway. Our results have shown alternative isoforms of STING counteract RNA virus infection in different ways.

Footnotes

  • This work was supported by the National Natural Science Foundation of China (U1402224, U1902215, and 81571998), the West Light Foundation of the Chinese Academy of Sciences (Light of West China Program xbzg-zdsys-201909) and the Yunnan Department of Science and Technology, Applied Basic Research Foundation of Yunnan Province (Yunnan Province Applied and Basic Research Foundation) (2016FB028 and 2018FB046).

  • The online version of this article contains supplemental material.

  • Received October 31, 2019.
  • Accepted April 15, 2020.
  • Copyright © 2020 by The American Association of Immunologists, Inc.

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The Journal of Immunology: 206 (3)
The Journal of Immunology
Vol. 206, Issue 3
1 Feb 2021
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An Alternative Splicing of Tupaia STING Modulated Anti-RNA Virus Responses by Targeting MDA5-LGP2 and IRF3
Ling Xu, Dandan Yu, Li Peng, Yong Wu, Yu Fan, Tianle Gu, Yu-Lin Yao, Jin Zhong, Xinwen Chen, Yong-Gang Yao
The Journal of Immunology May 6, 2020, ji1901320; DOI: 10.4049/jimmunol.1901320

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An Alternative Splicing of Tupaia STING Modulated Anti-RNA Virus Responses by Targeting MDA5-LGP2 and IRF3
Ling Xu, Dandan Yu, Li Peng, Yong Wu, Yu Fan, Tianle Gu, Yu-Lin Yao, Jin Zhong, Xinwen Chen, Yong-Gang Yao
The Journal of Immunology May 6, 2020, ji1901320; DOI: 10.4049/jimmunol.1901320
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