Phosphorylation of VP1 Mediated by CDK1-Cyclin B1 Facilitates Infectious Bursal Disease Virus Replication.
Phosphorylation of VP1 Mediated by CDK1-Cyclin B1 Facilitates Infectious Bursal Disease Virus Replication.
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CDK 1-Cyclin B1介导的VP 1磷酸化促进传染性法氏囊病病毒复制
DOI：
10.1128/jvi.01941-22
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发表时间：
2023-01-31
影响因子：
5.4
通讯作者：
Wu, Huansheng
中科院分区：
文献类型：
--
作者：
Hu, Xifeng;Chen, Zheng;Wu, Xiangdong;Ding, Zhen;Huang, Yu;Fu, Qiuling;Chen, Zhen;Wu, Huansheng
关键词：
传染性法氏囊病病毒（IBDV）是双链RNA（dsRNA）病毒，属于双RNA病毒科中的禽双RNA病毒属。它可导致免疫系统受损的幼禽接种严重失败。VP 1蛋白的翻译后修饰对于病毒RNA转录、基因组复制和病毒增殖是必需的。迄今为止，关于IBDV VP 1磷酸化的确切机制及其在病毒生命周期中的意义的信息很少。在这里，我们提供了几条线的证据表明，细胞周期蛋白依赖性激酶1（CDK 1）-细胞周期蛋白B1复合物磷酸化VP 1，这有利于病毒复制。我们发现，CDK 1-cyclin B1特异性地与VP 1相互作用，并磷酸化位于N-末端7SPAQ 10区域的丝氨酸7残基上的VP 1，其遵循CDK 1的最佳磷酸化基序p-S/T-P。此外，IBDV感染驱动CDK 1-cyclin B1的细胞质积累，其与VP 1共定位，支持CDK 1-cyclin B1的激酶活性。用CDK 1抑制剂RO 3306治疗并敲低CDK 1-cyclin B1严重破坏了VP 1的聚合酶活性，导致病毒复制减少。此外，与野生型（WT）IBDV相比，S7 A突变体重组IBDV的复制显著降低。因此，CDK 1-细胞周期蛋白B1是磷酸化IBDV VP 1丝氨酸7的关键酶，这对于VP 1的聚合酶活性和病毒复制都是必需的。传染性法氏囊病病毒仍然对全球家禽养殖业构成巨大的经济威胁。关于病毒基因组复制步骤的详细信息对于开发抗病毒疗法是必不可少的。磷酸化是几种病毒蛋白中常见的翻译后修饰。关于VP 1磷酸化的意义及其在调节病毒生命周期中的作用，缺乏相关信息。在这项研究中，我们发现CDK 1-cyclin B1在细胞质中积累，并磷酸化丝氨酸7上的VP 1。CDK 1抑制剂的存在和CDK 1-cyclin B1的沉默降低了IBDV的复制。VP 1丝氨酸7突变为丙氨酸降低了VP 1聚合酶活性，破坏了病毒的生命周期，这表明该残基具有重要的功能。我们的研究为VP 1磷酸化的调控机制提供了新的见解。
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 7SPAQ10 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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