title: Influenza A virus NS1 induces G0/G1 cell cycle arrest by inhibiting the expression and activity of RhoA protein.
abstract: Influenza A virus is an important pathogenic virus known to induce host cell cycle arrest in G(0)/G(1) phase and create beneficial conditions for viral replication. However, how the virus achieves arrest remains unclear. We investigated the mechanisms underlying this process and found that the nonstructural protein 1 (NS1) is required. Based on this finding, we generated a viable influenza A virus (H1N1) lacking the entire NS1 gene to study the function of this protein in cell cycle regulation. In addition to some cell cycle regulators that were changed, the concentration and activity of RhoA protein, which is thought to be pivotal for G(1)/S phase transition, were also decreased with overexpressing NS1. And in the meantime, the phosphorylation level of cell cycle regulator pRb, downstream of RhoA kinase, was decreased in an NS1-dependent manner. These findings indicate that the NS1 protein induces G(0)/G(1) cell cycle arrest mainly through interfering with the RhoA/pRb signaling cascade, thus providing favorable conditions for viral protein accumulation and replication. We further investigated the NS1 protein of avian influenza virus (H5N1) and found that it can also decrease the expression and activity of RhoA, suggesting that the H5N1 virus may affect the cell cycle through the same mechanism. The NS1/RhoA/pRb cascade, which can induce the G(0)/G(1) cell cycle arrest identified here, provides a unified explanation for the seemingly different NS1 functions involved in viral replication events. Our findings shed light on the mechanism of influenza virus replication and open new avenues for understanding the interaction between pathogens and hosts.
authors.affiliation: Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.forename: Qingtao
authors.initials: Q
authors.lastname: Wang
authors.forename: Shuai
authors.initials: S
authors.lastname: Chen
authors.forename: Shijuan
authors.initials: S
authors.lastname: Gao
authors.forename: Liping
authors.initials: L
authors.lastname: Song
authors.forename: Pengyu
authors.initials: P
authors.lastname: Liu
authors.forename: Wenlin
authors.initials: W
authors.lastname: Huang
mesh_terms: D000818:Animals; D002460:Cell Line; D004847:Epithelial Cells / Q000821:virology; D059585:G1 Phase Cell Cycle Checkpoints; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000472:pathogenicity*; D053124:Influenza A Virus, H5N1 Subtype / Q000472:pathogenicity*; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D037521:Virulence Factors / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors*
chemical_list: C085820:INS1 protein, influenza virus; D017361:Viral Nonstructural Proteins; D037521:Virulence Factors; D020742:rhoA GTP-Binding Protein