CypA Regulates AIP4-Mediated M1 Ubiquitination of Influenza A Virus |
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| Authors: | Madina Mahesutihan Weinan Zheng Liang Cui Yun Li Pengtao Jiao Wenxian Yang Wei Liu Jing Li Wenhui Fan Limin Yang Wenjun Liu Lei Sun |
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| Institution: | 1.CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology,Chinese Academy of Sciences,Beijing,China;2.University of Chinese Academy of Sciences,Beijing,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,China;4.College of Life Sciences,Henan Agricultural University,Zhengzhou,China |
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| 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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