Many viral proteins form biomolecular condensates via liquid-liquid phase separation (LLPS) to support viral replication and evade host antiviral responses, and thus, they are potential targets for designing antivirals. In the case of nonenveloped positive-sense RNA viruses, forming such condensates for viral replication is unclear and less understood. Human noroviruses (HuNoVs) are positive-sense RNA viruses that cause epidemic and sporadic gastroenteritis worldwide. Here, we show that the RNA-dependent RNA polymerase (RdRp) of pandemic GII.4 HuNoV forms distinct condensates that exhibit all the signature properties of LLPS with sustained polymerase activity and the capability of recruiting components essential for viral replication. We show that such condensates are formed in HuNoV-infected human intestinal enteroid cultures and are the sites for genome replication. Our studies demonstrate the formation of phase-separated condensates as replication factories in a positive-sense RNA virus, which plausibly is an effective mechanism to dynamically isolate RdRp replicating the genomic RNA from interfering with the ribosomal translation of the same RNA.

中文翻译：

---

主要人诺如病毒的 RNA 依赖性 RNA 聚合酶形成液-液相缩合物作为病毒复制工厂


许多病毒蛋白通过液-液相分离 （LLPS） 形成生物分子缩合物，以支持病毒复制并逃避宿主抗病毒反应，因此，它们是设计抗病毒药物的潜在靶标。在无包膜正义 RNA 病毒的情况下，形成这种浓缩物用于病毒复制尚不清楚，也不太清楚。人诺如病毒 （HuNoV） 是正义 RNA 病毒，可在世界范围内引起流行性和散发性胃肠炎。在这里，我们表明大流行 GII.4 HuNoV 的 RNA 依赖性 RNA 聚合酶 （RdRp） 形成不同的凝聚物，这些缩合物表现出 LLPS 的所有特征特性，具有持续的聚合酶活性和募集病毒复制所必需的成分的能力。我们表明，这种凝聚物是在 HuNoV 感染的人肠道类肠培养物中形成的，并且是基因组复制的位点。我们的研究表明，在正义 RNA 病毒中形成相分离的凝聚物作为复制工厂，这似乎是一种动态分离复制基因组 RNA 的 RdRp 干扰相同 RNA 的核糖体翻译的有效机制。