CypA Regulates AIP4-Mediated M1 Ubiquitination of Influenza A Virus
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.
KeywordsInfluenza A virus (IAV) Ubiquitination Cyclophilin A (CypA) AIP4 M1
This work was supported by grants from the National Natural Science Foundation of China (31630079, 31672531, 31572526, and 31802164), the National Key R&D Program of China (2016YFD0500206, 2015BAD11B02), the Strategic Priority Research Program of Chinese Academy of Sciences (XDB29010000), the National Science and Technology Major Project (2018ZX10101004), and the Emergency Technology Research Issue on Prevention and Control for Human Infection with A (H7N9) Avian Influenza Virus (10600100000015001206). Wenjun Liu is the principal investigator of the Innovative Research Group of National Natural Science Foundation of China (Grant No. 81621091).
LS and Wenjun Liu supervised the project, designed the study, and analyzed the data; MM and LS were responsible for planning and conducting the experimental work, and wrote the manuscript; WZ, Wei Liu and WF provided the technical support; LC, YL, PJ and WY participated in part of experimental work. JL and LY analyzed the data.
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Conflict of interest
The authors declare that they have no conflict of interest.
Animal and Human Rights Statement
This article does not contain any studies with human or animal subjects performed by any of the authors.
- Liu D, Shi W, Shi Y, Wang D, Xiao H, Li W, Bi Y, Wu Y, Li X, Yan J, Liu W, Zhao G, Yang W, Wang Y, Ma J, Shu Y, Lei F, Gao GF (2013) Origin and diversity of novel avian influenza A H7N9 viruses causing human infection: phylogenetic, structural, and coalescent analyses. Lancet 381:1926–1932CrossRefGoogle Scholar