Departments of Immunology and Microbial Science and Molecular Biology, and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2011 Feb 8;108(6):2396-401. doi: 10.1073/pnas.1016404108. Epub 2011 Jan 24.
Lassa fever virus, a member of the family Arenaviridae, is a highly endemic category A pathogen that causes 300,000-500,000 infections per year in Western Africa. The arenaviral nucleoprotein NP has been implicated in suppression of the host innate immune system, but the mechanism by which this occurs has remained elusive. Here we present the crystal structure at 1.5 Å of the immunosuppressive C-terminal portion of Lassa virus NP and illustrate that, unexpectedly, its 3D fold closely mimics that of the DEDDh family of exonucleases. Accompanying biochemical experiments illustrate that NP indeed has a previously unknown, bona fide exonuclease activity, with strict specificity for double-stranded RNA substrates. We further demonstrate that this exonuclease activity is essential for the ability of NP to suppress translocation of IFN regulatory factor 3 and block activation of the innate immune system. Thus, the nucleoprotein is a viral exonuclease with anti-immune activity, and this work provides a unique opportunity to combat arenaviral infections.
拉萨热病毒是沙粒病毒科的一种病毒，是一种高度地方性的 A 类病原体，每年在西非导致 30 万至 50 万例感染。沙粒病毒核蛋白 NP 被认为参与抑制宿主先天免疫系统，但这种情况发生的机制仍然难以捉摸。在这里，我们展示了拉萨病毒 NP 的免疫抑制 C 末端部分的 1.5Å 晶体结构，并说明出乎意料的是，它的 3D 折叠与 DEDDh 家族的外切核酸酶非常相似。伴随的生化实验表明，NP 确实具有以前未知的、真正的外切核酸酶活性，对双链 RNA 底物具有严格的特异性。我们进一步证明，这种外切核酸酶活性对于 NP 抑制 IFN 调节因子 3 易位和阻断先天免疫系统激活的能力至关重要。因此，核蛋白是一种具有抗病毒活性的病毒外切核酸酶，这项工作为对抗沙粒病毒感染提供了一个独特的机会。
