PDF(Pubmed)
Abstract：
Metabolism in host cells can be modulated after viral infection, favoring viral survival or clearance. Here, we report that lipid droplet (LD) synthesis in host cells can be modulated by yin yang 1 (YY1) after porcine reproductive and respiratory syndrome virus (PRRSV) infection, resulting in active antiviral activity. As a ubiquitously distributed transcription factor, there was increased expression of YY1 upon PRRSV infection both in vitro and in vivo. YY1 silencing promoted the replication of PRRSV, whereas YY1 overexpression inhibited PRRSV replication. PRRSV infection led to a marked increase in LDs, while YY1 knockout inhibited LD synthesis, and YY1 overexpression enhanced LD accumulation, indicating that YY1 reprograms PRRSV infection-induced intracellular LD synthesis. We also showed that the viral components do not colocalize with LDs during PRRSV infection, and the effect of exogenously induced LD synthesis on PRRSV replication is nearly lethal. Moreover, we demonstrated that YY1 affects the synthesis of LDs by regulating the expression of lipid metabolism genes. YY1 negatively regulates the expression of fatty acid synthase (FASN) to weaken the fatty acid synthesis pathway and positively regulates the expression of peroxisome proliferator-activated receptor gamma (PPARγ) to promote the synthesis of LDs, thus inhibiting PRRSV replication. These novel findings indicate that YY1 plays a crucial role in regulating PRRSV replication by reprogramming LD synthesis. Therefore, our study provides a novel mechanism of host resistance to PRRSV and suggests potential new antiviral strategies against PRRSV infection.IMPORTANCEPorcine reproductive and respiratory virus (PRRSV) has caused incalculable economic damage to the global pig industry since it was first discovered in the 1980s. However, conventional vaccines do not provide satisfactory protection. It is well known that viruses are parasitic pathogens, and the completion of their replication life cycle is highly dependent on host cells. A better understanding of host resistance to PRRSV infection is essential for developing safe and effective strategies to control PRRSV. Here, we report a crucial host antiviral molecule, yin yang 1 (YY1), which is induced to be expressed upon PRRSV infection and subsequently inhibits virus replication by reprogramming lipid droplet (LD) synthesis through transcriptional regulation. Our work provides a novel antiviral mechanism against PRRSV infection and suggests that targeting YY1 could be a new strategy for controlling PRRSV.
摘要：
宿主细胞中的代谢可以在病毒感染后被调节，有利于病毒存活或清除。这里,我们报道了猪繁殖与呼吸综合征病毒（PRRSV）感染后，阴阳1（YY1）可以调节宿主细胞内脂滴（LD）的合成，导致活跃的抗病毒活性。作为一种广泛分布的转录因子，在体外和体内PRRSV感染后，YY1的表达增加。YY1沉默促进了PRRSV的复制，而YY1过表达抑制PRRSV复制。PRRSV感染导致LDs明显增加，而YY1敲除抑制LD合成，YY1过表达增强了LD的积累，表明YY1重编程PRRSV感染诱导的细胞内LD合成。我们还表明，在PRRSV感染期间，病毒成分不与LD共定位，外源诱导的LD合成对PRRSV复制的影响几乎是致命的。此外，我们证明YY1通过调节脂质代谢基因的表达影响LDs的合成。YY1负调控脂肪酸合成酶(FASN)的表达削弱脂肪酸合成途径,正调控过氧化物酶体增殖物激活受体γ(PPARγ)的表达促进LDs的合成,从而抑制PRRSV复制。这些新发现表明YY1通过重编程LD合成在调节PRRSV复制中起关键作用。因此,我们的研究提供了宿主对PRRSV耐药的新机制，并提出了针对PRRSV感染的潜在新抗病毒策略。自上世纪80年代首次发现猪繁殖与呼吸道病毒(PRRSV)以来,对全球养猪业造成了无法估量的经济损失。然而,常规疫苗不能提供令人满意的保护。众所周知，病毒是寄生虫病原体，其复制生命周期的完成高度依赖于宿主细胞。更好地了解宿主对PRRSV感染的抗性对于开发控制PRRSV的安全有效策略至关重要。这里,我们报告了一个关键的宿主抗病毒分子，阴阳1（YY1），其在PRRSV感染时被诱导表达,并随后通过转录调节重编程脂滴(LD)合成来抑制病毒复制。我们的工作提供了一种针对PRRSV感染的新型抗病毒机制，并表明靶向YY1可能是控制PRRSV的新策略。
