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Volume 33 Issue 5
October 2018
    Citation: Madina Mahesutihan, Weinan Zheng, Liang Cui, Yun Li, Pengtao Jiao, Wenxian Yang, Wei Liu, Jing Li, Wenhui Fan, Limin Yang, Wenjun Liu, Lei Sun. CypA Regulates AIP4-Mediated M1 Ubiquitination of Influenza A Virus .VIROLOGICA SINICA, 2018, 33(5) : 440-448.  http://dx.doi.org/10.1007/s12250-018-0058-6
    shu

    CypA Regulates AIP4-Mediated M1 Ubiquitination of Influenza A Virus

    cstr: 32224.14.s12250-018-0058-6
    • 1.

      CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China

    • 2.

      University of Chinese Academy of Sciences, Beijing 100049, China

    • 3.

      State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources and Laboratory of Animal Infectious Diseases, College of Animal Sciences and Veterinary Medicine, Guangxi University, Nanning 530004, China

    • 4.

      College of Life Sciences, Henan Agricultural University, Zhengzhou 450002, China

    • Corresponding author: Wenjun Liu, liuwj@im.ac.cn, ORCID: 0000-0002-1590-7380
      Lei Sun, sunlei362@im.ac.cn, ORCID: 0000-0003-0141-2093
    • Received Date: 16 July 2018
      Accepted Date: 13 September 2018
      Published Date: 16 October 2018
      Available online: 01 October 2018
    • Cyclophilin A (CypA) is a peptidyl-prolyl cis/trans isomerase that interacts with the matrix protein (M1) of influenza A virus (IAV) and restricts virus replication by regulating the ubiquitin–proteasome-mediated degradation of M1. However, the mechanism by which CypA regulates M1 ubiquitination remains unknown. In this study, we reported that E3 ubiquitin ligase AIP4 promoted K48-linked ubiquitination of M1 at K102 and K104, and accelerated ubiquitin–proteasome-mediated degradation of M1. The recombinant IAV with mutant M1 (K102R/K104R) could not be rescued, suggesting that the ubiquitination of M1 at K102/K104 was essential for IAV replication. Furthermore, CypA inhibited AIP4-mediated M1 ubiquitination by impairing the interaction between AIP4 and M1. More importantly, both the mutations of M1 (K102R/ K104R) and CypA inhibited the nuclear export of M1, indicating that CypA regulates the cellular localization of M1 via inhibition of AIP4-mediated M1 ubiquitination at K102 and K104, which results in the reduced replication of IAV. Collectively, our findings reveal a novel ubiquitination-based mechanism by which CypA regulates the replication of IAV.
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      CypA Regulates AIP4-Mediated M1 Ubiquitination of Influenza A Virus

        Corresponding author: Wenjun Liu, liuwj@im.ac.cn
        Corresponding author: Lei Sun, sunlei362@im.ac.cn
      • 1. CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
      • 2. University of Chinese Academy of Sciences, Beijing 100049, China
      • 3. State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources and Laboratory of Animal Infectious Diseases, College of Animal Sciences and Veterinary Medicine, Guangxi University, Nanning 530004, China
      • 4. College of Life Sciences, Henan Agricultural University, Zhengzhou 450002, China
      • Received Date: 16 July 2018
      • Accepted Date: 13 September 2018
      • Published Date: 16 October 2018

      Abstract: Cyclophilin A (CypA) is a peptidyl-prolyl cis/trans isomerase that interacts with the matrix protein (M1) of influenza A virus (IAV) and restricts virus replication by regulating the ubiquitin–proteasome-mediated degradation of M1. However, the mechanism by which CypA regulates M1 ubiquitination remains unknown. In this study, we reported that E3 ubiquitin ligase AIP4 promoted K48-linked ubiquitination of M1 at K102 and K104, and accelerated ubiquitin–proteasome-mediated degradation of M1. The recombinant IAV with mutant M1 (K102R/K104R) could not be rescued, suggesting that the ubiquitination of M1 at K102/K104 was essential for IAV replication. Furthermore, CypA inhibited AIP4-mediated M1 ubiquitination by impairing the interaction between AIP4 and M1. More importantly, both the mutations of M1 (K102R/ K104R) and CypA inhibited the nuclear export of M1, indicating that CypA regulates the cellular localization of M1 via inhibition of AIP4-mediated M1 ubiquitination at K102 and K104, which results in the reduced replication of IAV. Collectively, our findings reveal a novel ubiquitination-based mechanism by which CypA regulates the replication of IAV.

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