Department of Veterinary Medicine and Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD, United States of America.
Department of Molecular and Cellular Biology, University of Maryland, College Park, MD, United States of America.
PLoS Pathog. 2018 Aug 27;14(8):e1007280. doi: 10.1371/journal.ppat.1007280. eCollection 2018 Aug.
Rapid development of complex membranous replication structures is a hallmark of picornavirus infections. However, neither the mechanisms underlying such dramatic reorganization of the cellular membrane architecture, nor the specific role of these membranes in the viral life cycle are sufficiently understood. Here we demonstrate that the cellular enzyme CCTα, responsible for the rate-limiting step in phosphatidylcholine synthesis, translocates from the nuclei to the cytoplasm upon infection and associates with the replication membranes, resulting in the rerouting of lipid synthesis from predominantly neutral lipids to phospholipids. The bulk supply of long chain fatty acids necessary to support the activated phospholipid synthesis in infected cells is provided by the hydrolysis of neutral lipids stored in lipid droplets. Such activation of phospholipid synthesis drives the massive membrane remodeling in infected cells. We also show that complex membranous scaffold of replication organelles is not essential for viral RNA replication but is required for protection of virus propagation from the cellular anti-viral response, especially during multi-cycle replication conditions. Inhibition of infection-specific phospholipid synthesis provides a new paradigm for controlling infection not by suppressing viral replication but by making it more visible to the immune system.
复杂膜复制结构的快速发展是微小核糖核酸病毒感染的一个标志。然而，细胞膜结构的这种剧烈重组的潜在机制，以及这些膜在病毒生命周期中的具体作用，还没有得到充分的理解。在这里，我们证明了负责磷酸胆碱合成限速步骤的细胞酶 CCTα 在感染后从细胞核易位到细胞质，并与复制膜结合，导致脂质合成从主要的中性脂质重新定向到磷脂。大量长链脂肪酸的供应对于支持感染细胞中激活的磷脂合成是必需的，这些脂肪酸是通过水解储存在脂滴中的中性脂质提供的。这种磷脂合成的激活驱动了感染细胞中的大量膜重塑。我们还表明，复制细胞器的复杂膜支架对于病毒 RNA 复制不是必需的，但对于保护病毒的传播免受细胞抗病毒反应是必需的，特别是在多周期复制条件下。抑制感染特异性磷脂合成为控制感染提供了一个新的范例，不是通过抑制病毒复制，而是通过使病毒更易被免疫系统发现。
