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Phosphorylation of VP1 Mediated by CDK1-Cyclin B1 Facilitates Infectious Bursal Disease Virus Replication

文献类型： 外文期刊

作者： Hu, Xifeng 1 ; Chen, Zheng 1 ; Wu, Xiangdong 1 ; Ding, Zhen 1 ; Huang, Yu 3 ; Fu, Qiuling 3 ; Chen, Zhen 3 ; Wu, Huansheng 1 ;

作者机构： 1.Jiangxi Agr Univ, Coll Anim Sci & Technol, Dept Vet Prevent Med, Nanchang, Peoples R China

2.Jiangxi Agr Univ, Coll Anim Sci & Technol, Jiangxi Prov Key Lab Anim Hlth, Nanchang, Peoples R China

3.Fujian Acad Agr Sci, Inst Anim Husb & Vet Med, Fuzhou, Peoples R China

关键词： IBDV VP1; CDK1-cyclin B1; phosphorylation; Ser7; polymerase activity; viral polymerase; host kinase; viral protein phosphorylation; virology; virus replication

期刊名称：JOURNAL OF VIROLOGY （ 影响因子：5.4； 五年影响因子：4.9 ）

ISSN： 0022-538X

年卷期： 2023 年 97 卷 1 期

页码：

收录情况： SCI

摘要： Infectious bursal disease virus still poses a great economic threat to the global poultry farming industry. Detailed information on the steps of viral genome replication is essential for the development of antiviral therapeutics. Infectious bursal disease virus (IBDV) is a double-stranded RNA (dsRNA) virus belonging to the genus Avibirnavirus in the family Birnaviridae. It can cause serious failure of vaccination in young poultry birds with impaired immune systems. Post-translational modifications of the VP1 protein are essential for viral RNA transcription, genome replication, and viral multiplication. Little information is available so far regarding the exact mechanism of phosphorylation of IBDV VP1 and its significance in the viral life cycle. Here, we provide several lines of evidence that the cyclin-dependent kinase 1 (CDK1)-cyclin B1 complex phosphorylates VP1, which facilitates viral replication. We show that the CDK1-cyclin B1 specifically interacts with VP1 and phosphorylates VP1 on the serine 7 residue, located in the N-terminal (7)SPAQ(10) region, which follows the optimal phosphorylation motif of CDK1, p-S/T-P. Additionally, IBDV infection drives the cytoplasmic accumulation of CDK1-cyclin B1, which co-localizes with VP1, supporting the kinase activity of CDK1-cyclin B1. Treatment with CDK1 inhibitor RO3306 and knockdown of CDK1-cyclin B1 severely disrupts the polymerase activity of VP1, resulting in diminished viral replication. Moreover, the replication of S7A mutant recombinant IBDV was significantly decreased compared to that of wild-type (WT) IBDV. Thus, CDK1-cyclin B1 is a crucial enzyme which phosphorylates IBDV VP1 on serine 7, which is necessary both for the polymerase activity of VP1 and for viral replication.IMPORTANCE Infectious bursal disease virus still poses a great economic threat to the global poultry farming industry. Detailed information on the steps of viral genome replication is essential for the development of antiviral therapeutics. Phosphorylation is a common post-translational modification in several viral proteins. There is a lack of information regarding the significance of VP1 phosphorylation and its role in modulating the viral life cycle. In this study, we found that CDK1-cyclin B1 accumulates in the cytoplasm and phosphorylates VP1 on serine 7. The presence of a CDK1 inhibitor and the silencing of CDK1-cyclin B1 decrease IBDV replication. The mutation of VP1 serine 7 to alanine reduces VP1 polymerase activity, disrupting the viral life cycle, which suggests that this residue serves an essential function. Our study offers novel insights into the regulatory mechanism of VP1 phosphorylation.

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