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Virologica Sinica, 33 (5) : 440, 2018
Research Article
CypA Regulates AIP4-Mediated M1 Ubiquitination of Influenza A Virus
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
 Correspondence: liuwj@im.ac.cn;sunlei362@im.ac.cn
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.
Received: 16 Jul 2018  Accepted: 13 Sep 2018  Published online: 16 Oct 2018
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