With no available therapies, infections with Zika virus (ZIKV) constitute a major public health concern as they can lead to congenital microcephaly. In order to generate an intracellular environment favourable to viral replication, ZIKV induces endomembrane remodelling and the morphogenesis of replication factories via enigmatic mechanisms. In this study, we identified the AAA+ type ATPase valosin‐containing protein (VCP) as a cellular interaction partner of ZIKV non‐structural protein 4B (NS4B). Importantly, its pharmacological inhibition as well as the expression of a VCP dominant‐negative mutant impaired ZIKV replication. In infected cells, VCP is relocalised to large ultrastructures containing both NS4B and NS3, which are reminiscent of dengue virus convoluted membranes. Moreover, short treatment with the VCP inhibitors NMS‐873 or CB‐5083 drastically decreased the abundance and size of ZIKV‐induced convoluted membranes. Furthermore, NMS‐873 treatment inhibited ZIKV‐induced mitochondria elongation previously reported to be physically and functionally linked to convoluted membranes in case of the closely related dengue virus. Finally, VCP inhibition resulted in enhanced apoptosis of ZIKV‐infected cells strongly suggesting that convoluted membranes limit virus‐induced cytopathic effects. Altogether, this study identifies VCP as a host factor required for ZIKV life cycle and more precisely, for the maintenance of viral replication factories. Our data further support a model in which convoluted membranes regulate ZIKV life cycle by impacting on mitochondrial functions and ZIKV‐induced death signals in order to create a cytoplasmic environment favourable to viral replication.

中文翻译：

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含有 Valosin 的蛋白 ATP 酶活性调节寨卡病毒复制细胞器的形态发生和病毒诱导的细胞死亡

由于没有可用的治疗方法，寨卡病毒 (ZIKV) 感染构成了主要的公共卫生问题，因为它们可能导致先天性小头畸形。为了产生有利于病毒复制的细胞内环境，ZIKV 通过神秘的机制诱导内膜重塑和复制工厂的形态发生。在这项研究中，我们确定了 AAA+ 型 ATPase valosin 蛋白 (VCP) 作为 ZIKV 非结构蛋白 4B (NS4B) 的细胞相互作用伙伴。重要的是，它的药理抑制作用以及 VCP 显性负突变体的表达会损害 ZIKV 的复制。在受感染的细胞中，VCP 重新定位到包含 NS4B 和 NS3 的大型超微结构，这让人联想到登革热病毒的卷曲膜。而且，用 VCP 抑制剂 NMS-873 或 CB-5083 进行短期治疗，可显着降低 ZIKV 诱导的卷曲膜的丰度和大小。此外，NMS-873 治疗抑制了 ZIKV 诱导的线粒体伸长，此前报道称，在密切相关的登革热病毒的情况下，这在物理和功能上与卷曲的膜相关。最后，VCP 抑制导致 ZIKV 感染细胞的凋亡增强，这强烈表明卷曲的膜限制了病毒诱导的细胞病变效应。总之，这项研究将 VCP 确定为 ZIKV 生命周期所需的宿主因素，更准确地说，是维持病毒复制工厂所需的宿主因素。