Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA.
J Virol. 2011 Dec;85(24):13038-48. doi: 10.1128/JVI.05834-11. Epub 2011 Oct 5.
Several arenaviruses cause hemorrhagic fever (HF) disease in humans that is associated with high morbidity and significant mortality. Arenavirus nucleoprotein (NP), the most abundant viral protein in infected cells and virions, encapsidates the viral genome RNA, and this NP-RNA complex, together with the viral L polymerase, forms the viral ribonucleoprotein (vRNP) that directs viral RNA replication and gene transcription. Formation of infectious arenavirus progeny requires packaging of vRNPs into budding particles, a process in which arenavirus matrix-like protein (Z) plays a central role. In the present study, we have characterized the NP-Z interaction for the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV). The LCMV NP domain that interacted with Z overlapped with a previously documented C-terminal domain that counteracts the host type I interferon (IFN) response. However, we found that single amino acid mutations that affect the anti-IFN function of LCMV NP did not disrupt the NP-Z interaction, suggesting that within the C-terminal region of NP different amino acid residues critically contribute to these two distinct and segregable NP functions. A similar NP-Z interaction was confirmed for the HF arenavirus Lassa virus (LASV). Notably, LCMV NP interacted similarly with both LCMV Z and LASV Z, while LASV NP interacted only with LASV Z. Our results also suggest the presence of a conserved protein domain within NP but with specific amino acid residues playing key roles in determining the specificity of NP-Z interaction that may influence the viability of reassortant arenaviruses. In addition, this NP-Z interaction represents a potential target for the development of antiviral drugs to combat human-pathogenic arenaviruses.
几种沙粒病毒可引起人类出血热（HF）疾病，这种疾病与高发病率和显著的死亡率有关。沙粒病毒核蛋白（NP）是感染细胞和病毒粒子中最丰富的病毒蛋白，它包裹着病毒基因组 RNA，NP-RNA 复合物与病毒 L 聚合酶一起形成病毒核糖核蛋白（vRNP），指导病毒 RNA 复制和基因转录。形成有感染力的沙粒病毒子代需要将 vRNP 包装到出芽颗粒中，这个过程中沙粒病毒基质样蛋白（Z）起着核心作用。在本研究中，我们对原型沙粒病毒淋巴细胞性脉络丛脑膜炎病毒（LCMV）的 NP-Z 相互作用进行了表征。与 Z 相互作用的 LCMV NP 结构域与先前报道的一个 C 末端结构域重叠，该结构域可拮抗宿主的 I 型干扰素（IFN）反应。然而，我们发现，影响 LCMV NP 抗 IFN 功能的单个氨基酸突变并没有破坏 NP-Z 相互作用，这表明 NP 的 C 末端区域中的不同氨基酸残基对这两种截然不同且可分离的 NP 功能具有重要贡献。我们还证实了 HF 沙粒病毒拉萨病毒（LASV）的 NP-Z 相互作用。值得注意的是，LCMV NP 与 LCMV Z 和 LASV Z 均相互作用，而 LASV NP 仅与 LASV Z 相互作用。我们的研究结果还表明 NP 中存在一个保守的蛋白结构域，但具有特定的氨基酸残基在决定 NP-Z 相互作用的特异性方面起着关键作用，这可能会影响重组沙粒病毒的存活能力。此外，这种 NP-Z 相互作用可能是开发抗人类致病性沙粒病毒的抗病毒药物的潜在靶点。
