CypA Regulates AIP4-Mediated M1 Ubiquitination of Influenza A Virus

  • Virol Sin. 2018 Oct;33(5):440-448. doi: 10.1007/s12250-018-0058-6.
Madina Mahesutihan  1  2 ,  Weinan Zheng  1 ,  Liang Cui  1  2 ,  Yun Li  1 ,  Pengtao Jiao  3 ,  Wenxian Yang  1  2 ,  Wei Liu  4 ,  Jing Li  1 ,  Wenhui Fan  1 ,  Limin Yang  1 ,  Wenjun Liu  5  6 ,  Lei Sun  7  8
Affiliations
  • 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.
  • 5. CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China. [email protected].
  • 6. University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • 7. CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China. [email protected].
  • 8. University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
PMID: 30328013 DOI: 10.1007/s12250-018-0058-6
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.

Keywords
AIP4; Cyclophilin A (CypA); Influenza A virus (IAV); M1; Ubiquitination.