Cellular biological examination of relationship between viral and host factors and development of therapeutic strategy PML

病毒与宿主因素之间关系的细胞生物学检查以及 PML 治疗策略的制定

• 批准号: 21390111
• 负责人: SAWA Hirofumi
• 金额: $ 11.98万
• 依托单位: Hokkaido University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21390111/
• 关键词: 細胞; JCウイルス; 宿主因子; PML

The human polyomavirus JC virus (JCV) is the causative agent of progressive multifocal leukoencephalopathy (PML). The JCV encoded agnoprotein has been shown to act as a viroporin, promoting the release of progeny virions. We demonstrate that the JCV agnoprotein specifically interacts with AP-3. This interaction interrupts AP-3-mediated vesicular trafficking with suppression of the targeting of the protein to the lysosomal degradation pathway, and instead permitting the transport of agnoprotein to the cell surface. The findings demonstrate a unique viral-host factors interaction, and suggest that the viroporins of other viruses may also be highly regulated by specific interactions with host factors. In addition, JCV capsid consists of 72 pentameric capsomeres of a major structural protein VP1. We examined the role of cysteine residues in the VP1 expression by individually mutating the six cysteines. The C80A and C247A VP1 mutants showed greatly decreased Vpl expression. Our results suggest that regions of VP1 including Cys80 and Cys247 is essential for JCV virion assembly. These results may be applicable for development of therapeutic strategy for PML and other viral diseases.

人类多瘤病毒JC病毒（JCV）是进行性多灶性白质脑病（PML）的病原体。已显示JCV编码的未知蛋白充当病毒孔蛋白，促进子代病毒体的释放。我们证明了JCV的agnoprotein特异性地与AP-3相互作用。这种相互作用中断AP-3介导的囊泡运输，抑制蛋白质靶向溶酶体降解途径，而是允许未知蛋白转运到细胞表面。研究结果表明，一个独特的病毒-宿主因子的相互作用，并表明，其他病毒的病毒孔蛋白也可能受到高度调节的特定相互作用与宿主因子。此外，JCV衣壳由主要结构蛋白VP 1的72个五聚体衣壳组成。我们通过单独突变六个半胱氨酸来研究半胱氨酸残基在VP 1表达中的作用。C80 A和C247 A VP 1突变体显示Vpl表达大大降低。我们的研究结果表明，VP 1的区域，包括Cys 80和Cys 247是必不可少的JCV病毒粒子组装。这些结果可能适用于PML和其他病毒性疾病的治疗策略的发展。

项目成果

A novel deletion in JC virus agnoprotein causes productive infection of cortical pyramidal neurons.

JC 病毒无视蛋白的新缺失导致皮质锥体神经元的有效感染。

• 发表时间: 2010
• 作者: Dang X;Wuthrich C;Gordon J;Sawa H;Koralnik I
• 通讯作者: Koralnik I

Large T antigen promotes JC virus replication in G2 arrest by inducing G2 checkpoint signaling.

大 T 抗原通过诱导 G2 检查点信号传导，促进 G2 停滞中的 JC 病毒复制。

• 发表时间: 2010
• 作者: Orba Y;Suzuki T;Kimura T;Sawa H
• 通讯作者: Sawa H

Viroporin activity of JCV agnoprotein

JCV 无视蛋白的病毒孔蛋白活性

• 发表时间: 2009
• 作者: Suzuki T;Orba Y;Sunden Y;Kimura T;Sawa H
• 通讯作者: Sawa H

JCVウイルスAgnoproteinによるウイルス粒子の形態制御

JCV病毒Agno蛋白控制病毒颗粒形态

• 发表时间: 2009
• 作者: 鈴木忠樹;仙葉慎吾;大場靖子;寸田祐嗣;木村享史;長嶋和郎;澤洋文
• 通讯作者: 澤洋文

Disruption of intracellular vesicular trafficking by agnoprotein is essential for viroporin activity and JC virus replication

无视蛋白对细胞内囊泡运输的破坏对于病毒孔蛋白活性和 JC 病毒复制至关重要

• 发表时间: 2010
• 作者: Suzuki T;Orba Y;Makino Y;Okada Y;Sunden Y;Kimura T;Hasegawa H;Sata T;Hall WW;Sawa H
• 通讯作者: Sawa H