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TAR DNA-Binding Protein 43 is Cleaved by the Protease 3C of Enterovirus A71

  • RESEARCH ARTICLE
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Virologica Sinica

Abstract

Enterovirus A71 (EV-A71) is one of the etiological pathogens leading to hand, foot, and mouth disease (HFMD), which can cause severe neurological complications. The neuropathogenesis of EV-A71 infection is not well understood. The mislocalization and aggregation of TAR DNA-binding protein 43 (TDP-43) is the pathological hallmark of amyotrophic lateral sclerosis (ALS). However, whether TDP-43 was impacted by EV-A71 infection is unknown. This study demonstrated that TDP-43 was cleaved during EV-A71 infection. The cleavage of TDP-43 requires EV-A71 replication rather than the activated caspases due to viral infection. TDP-43 is cleaved by viral protease 3C between the residues 331Q and 332S, while mutated TDP-43 (Q331A) was not cleaved. In addition, mutated 3C which lacks the protease activity failed to induce TDP-43 cleavage. We also found that TDP-43 was translocated from the nucleus to the cytoplasm, and the mislocalization of TDP-43 was induced by viral protease 2A rather than 3C. Taken together, we demonstrated that TDP-43 was cleaved by viral protease and translocated to the cytoplasm during EV-A71 infection, implicating the possible involvement of TDP-43 in the pathogenesis of EV-A71infection.

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Acknowledgements

This study was supported by the National Natural Foundation of China (81672007 and 81971920 to Wenran Zhao, 81871652 to Zhaohua Zhong, and 81772188 to Yan Wang) and Health and Family Planning Commission of Heilongjiang Province (2017-158 to Xiaoman Wo). We are grateful to the help of Dr. Ying Wu (School of Life Sciences, Northeast Forestry University, Harbin, China) in viewing the images of fluorescence microscope.

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  1. Xiaoman Wo and Yuan Yuan contributed equally to this work.

Authors and Affiliations

  1. Department of Cell Biology, Harbin Medical University, Harbin, 150081, China

    Xiaoman Wo, Yuan Yuan, Yong Xu, Yao Wang, Shuoxuan Zhao & Wenran Zhao

  2. Department of Microbiology, Harbin Medical University, Harbin, 150081, China

    Yang Chen, Lexun Lin, Xiaoyan Zhong, Yan Wang & Zhaohua Zhong

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  1. Xiaoman Wo
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  2. Yuan Yuan
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  3. Yong Xu
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  4. Yang Chen
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  5. Yao Wang
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  6. Shuoxuan Zhao
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  7. Lexun Lin
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  8. Xiaoyan Zhong
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  9. Yan Wang
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  10. Zhaohua Zhong
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  11. Wenran Zhao
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Contributions

WZ and ZZ conceived the experiments, analyzed the data. WZ wrote the manuscript. XW, YY, and YX performed the majority of the laboratory work. Yao Wang and YC prepared and performed the immunofluorescence visualization. SZ and Yan Wang prepared of plasmids. LL and XZ prepared Enterovirus A71 for this study.

Corresponding authors

Correspondence to Zhaohua Zhong or Wenran Zhao.

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Wo, X., Yuan, Y., Xu, Y. et al. TAR DNA-Binding Protein 43 is Cleaved by the Protease 3C of Enterovirus A71. Virol. Sin. 36, 95–103 (2021). https://doi.org/10.1007/s12250-020-00262-x

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