Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Brno, Czech Republic.
J Virol. 2021 Jan 13;95(3). doi: 10.1128/JVI.01957-20.
parasites cause a variety of symptoms, including mucocutaneous leishmaniasis, which results in the destruction of the mucous membranes of the nose, mouth, and throat. The species of carrying RNA virus 1 (LRV1), from the family , are more likely to cause severe disease and are less sensitive to treatment than those that do not contain the virus. Although the importance of LRV1 for the severity of leishmaniasis was discovered a long time ago, the structure of the virus remained unknown. Here, we present a cryo-electron microscopy reconstruction of the virus-like particle of LRV1 determined to a resolution of 3.65 Å. The capsid has icosahedral symmetry and is formed by 120 copies of a capsid protein assembled in asymmetric dimers. RNA genomes of viruses from the family are synthetized, but not capped at the 5' end, by virus RNA polymerases. To protect viral RNAs from degradation, capsid proteins of the L-A totivirus cleave the 5' caps of host mRNAs, creating decoys to overload the cellular RNA quality control system. Capsid proteins of LRV1 form positively charged clefts, which may be the cleavage sites for the 5' cap of mRNAs. The putative RNA binding site of LRV1 is distinct from that of the related L-A virus. The structure of the LRV1 capsid enables the rational design of compounds targeting the putative decapping site. Such inhibitors may be developed into a treatment for mucocutaneous leishmaniasis caused by LRV1-positive species of Twelve million people worldwide suffer from leishmaniasis, resulting in more than 30 thousand deaths annually. The disease has several variants that differ in their symptoms. The mucocutaneous form, which leads to disintegration of the nasal septum, lips, and palate, is caused predominantly by parasites carrying RNA virus 1 (LRV1). Here, we present the structure of the LRV1 capsid determined using cryo-electron microscopy. Capsid proteins of a related totivirus, L-A virus, protect viral RNAs from degradation by cleaving the 5' caps of host mRNAs. Capsid proteins of LRV1 may have the same function. We show that the LRV1 capsid contains positively charged clefts that may be sites for the cleavage of mRNAs of cells. The structure of the LRV1 capsid enables the rational design of compounds targeting the putative mRNA cleavage site. Such inhibitors may be used as treatments for mucocutaneous leishmaniasis.
寄生虫可引起多种症状，包括黏膜皮肤利什曼病，这会导致鼻腔、口腔和喉咙的黏膜受损。携带 RNA 病毒 1（LRV1）的种属更易导致严重疾病，并且对治疗的敏感性低于不携带病毒的种属。尽管很久以前就发现了 LRV1 对利什曼病严重程度的重要性，但该病毒的结构仍不清楚。在这里，我们展示了 LRV1 病毒样颗粒的低温电子显微镜重建，分辨率为 3.65Å。衣壳具有二十面体对称性，由组装成非对称二聚体的 120 个衣壳蛋白组成。家族的病毒 RNA 基因组通过病毒 RNA 聚合酶合成，但在 5' 端不被加帽。为了保护病毒 RNA 免受降解，L-A totivirus 的衣壳蛋白切割宿主 mRNA 的 5' 帽，形成诱饵来使细胞的 RNA 质量控制系统过载。LRV1 的衣壳蛋白形成带正电荷的裂缝，这些裂缝可能是切割 mRNAs 5' 帽的位点。LRV1 的推定 RNA 结合位点与相关的 L-A 病毒不同。LRV1 衣壳的结构使针对推定脱帽位点的化合物的合理设计成为可能。这种抑制剂可能被开发成治疗由 LRV1 阳性种属引起的黏膜皮肤利什曼病的方法。全世界有 1200 万人患有利什曼病，每年导致超过 30000 人死亡。该疾病有几种变体，其症状不同。导致鼻中隔、嘴唇和上颚破裂的黏膜皮肤型主要由携带 RNA 病毒 1（LRV1）的寄生虫引起。在这里，我们展示了使用低温电子显微镜确定的 LRV1 衣壳结构。相关 totivirus L-A 病毒的衣壳蛋白通过切割宿主 mRNA 的 5' 帽来保护病毒 RNA 免受降解。LRV1 的衣壳蛋白可能具有相同的功能。我们表明，LRV1 衣壳包含带正电荷的裂缝，这些裂缝可能是切割细胞的 mRNAs 的位点。LRV1 衣壳的结构使针对推定的 mRNA 切割位点的化合物的合理设计成为可能。这种抑制剂可用作黏膜皮肤利什曼病的治疗方法。
