De novo fatty acid biosynthesis and HIV replication

摘要 HIV-1侵占宿主新陈代谢，创造有利于病毒复制的细胞环境。我们有 最近发现，哺乳动物脂肪酸合成酶(FASN)水平在感染HIV-1后增加，并且 在病毒蛋白表达之后的HIV复制的后期步骤需要FASN活性(例如， 蛋白质运输、病毒粒子组装或病毒粒子释放)。我们提议的研究的目标是确定如何 FASN活性和由此产生的从头脂肪酸(FA)影响HIV-1复制的后期阶段。该产品 在FASN中，棕榈酸酯是一种具有多种细胞作用的长链FA，也可以被修剪成肉豆蔻酸或 扩展到其他长链FA。长链脂肪酸具有许多细胞功能，包括在膜上的作用 亚细胞蛋白质定位的结构、能量储存和调控。这项建议集中在两个方面 可能中断HIV-1复制周期后期阶段的FASN介导的机制：生产 蛋白质翻译后修饰的脂类(AIM 1)，以及重组细胞脂质的FA的产生 组成(目标2)。如果HIV-1需要FASN活性来促进病毒蛋白运输或病毒粒子组装，我们 揭示了一种基本的机制，可以解释为什么许多包膜病毒需要FASN 要复制的活动。

ABSTRACT HIV-1 commandeers host metabolism to create a cellular environment favorable to viral replication. We have recently discovered that mammalian fatty acid synthase (FASN) levels increase following HIV-1 infection, and that FASN activity is required for a late step of HIV replication that is subsequent to viral protein expression (e.g. protein trafficking, virion assembly, or virion release). The goal of our proposed research is to determine how FASN activity and resulting de novo fatty acid (FA) production affect a late stage of HIV-1 replication. The product of FASN, palmitate, is a long chain FA that has multiple cellular roles, and can also be trimmed into myristate or extended into other long chain FAs. Long chain FAs have many cellular functions, including roles in membrane structure, energy storage, and regulation of subcellular protein localization. This proposal focuses on two plausible FASN-mediated mechanisms that could interrupt a late stage in the HIV-1 replication cycle: production of lipids for post-translational modification of proteins (AIM 1), and generation of FA to reconfigure cellular lipid composition (AIM 2). If HIV-1 requires FASN activity to facilitate viral protein trafficking or virion assembly, we will have revealed a fundamental mechanism that could explain why many enveloped viruses require FASN activity to replicate.