Szostek Olga, Schorsch Patrycja, Bender Daniela, Glitscher Mirco, Hildt Eberhard
Research Group, Paul-Ehrlich-Institute, 63225 Langen, Germany.
Digital Health Cluster, Hasso-Plattner-Institute, University of Potsdam, 14482 Potsdam, Germany.
Viruses. 2025 Jul 28;17(8):1052. doi: 10.3390/v17081052.
The life cycle of the hepatitis C virus (HCV) is closely linked to lipid metabolism. Recently, the stress defence transcription factor, nuclear factor erythroid 2 related factor-1 (Nrf1), has been described as a cholesterol sensor that protects the liver from excess cholesterol. Nrf1, like its homologue Nrf2, further responds to oxidative stress by binding with small Maf proteins (sMaf) to the promotor antioxidant response element (ARE). Given these facts, investigating the crosstalk between Nrf1 and HCV was a logical next step. In HCV-replicating cells, we observed reduced levels of Nrf1. Furthermore, activation of Nrf1-dependent target genes is impaired due to sMaf sequestration in replicase complexes. This results in a shortage of sMaf proteins in the nucleus, trapping Nrf1 at the replicase complexes and further limiting its function. Weakened Nrf1 activity contributes to impaired cholesterol removal, which occurs alongside an elevated intracellular cholesterol level and inhibited LXRα promoter activation. Furthermore, inhibition of Nrf1 activity correlated with a kinome profile characteristic of steatosis and enhanced inflammation-factors contributing to HCV pathogenesis. Our results indicate that activation of Nrf1-dependent target genes is impaired in HCV-positive cells. This, in turn, favours viral morphogenesis, as evidenced by enhanced replication and increased production of viral progeny.
丙型肝炎病毒（HCV）的生命周期与脂质代谢密切相关。最近，应激防御转录因子核因子红细胞2相关因子1（Nrf1）被描述为一种胆固醇传感器，可保护肝脏免受过量胆固醇的侵害。Nrf1与其同系物Nrf2一样，通过与小Maf蛋白（sMaf）结合到启动子抗氧化反应元件（ARE）上，进一步对氧化应激作出反应。鉴于这些事实，研究Nrf1与HCV之间的相互作用是合乎逻辑的下一步。在HCV复制细胞中，我们观察到Nrf1水平降低。此外，由于复制酶复合物中sMaf的隔离，Nrf1依赖性靶基因的激活受到损害。这导致细胞核中sMaf蛋白短缺，将Nrf1困在复制酶复合物中，并进一步限制其功能。Nrf1活性减弱导致胆固醇清除受损，同时细胞内胆固醇水平升高和LXRα启动子激活受到抑制。此外，Nrf1活性的抑制与脂肪变性的激酶组特征以及导致HCV发病机制的炎症因子增强相关。我们的结果表明，Nrf1依赖性靶基因的激活在HCV阳性细胞中受损。这反过来有利于病毒形态发生，如复制增强和病毒后代产量增加所证明的那样。
