CypA Regulates AIP4-Mediated M1 Ubiquitination of Influenza A Virus

• 来源期刊: 中国病毒学
• 年，卷（期）: 2018,（5）
• 页码范围: 440-448
• 页数: 9页
• 语种: 英文

摘要

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 K48-1inked 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.