SLC1A3 facilitates Newcastle disease virus replication by regulating glutamine catabolism

As obligate intracellular parasites, viruses rely completely on host metabolic machinery and hijack host nutrients for viral replication. Newcastle disease virus (NDV) causes acute, highly contagious avian disease and functions as an oncolytic agent. NDV efficiently replicates in both chicken and tumour cells. However, how NDV reprograms host cellular metabolism for its efficient replication is still ill-defined. We previously identified a significantly upregulated glutamate transporter gene, solute carrier family 1 member 3 (<i>SLC1A3</i>), during NDV infection via transcriptome analysis. To investigate the potential role of <i>SLC1A3</i> during NDV infection, we first confirmed the marked upregulation of <i>SLC1A3</i> in NDV-infected DF-1 or A549 cells through p53 and NF-κB pathways. Knockdown of <i>SLC1A3</i> inhibited NDV infection. Western blot analysis further confirmed that glutamine, but not glutamate, asparagine, or aspartate, was required for NDV replication. Metabolic flux data showed that NDV promotes the decomposition of glutamine into the tricarboxylic acid cycle. Importantly, the level of glutamate and glutaminolysis were reduced by <i>SLC1A3</i> knockdown, indicating that <i>SLC1A3</i> propelled glutaminolysis for glutamate utilization and NDV replication in host cells. Taken together, our data identify that <i>SLC1A3</i> serves as an important regulator for glutamine metabolism and is hijacked by NDV for its efficient replication during NDV infection. These results improve our understanding of the interaction between NDV and host cellular metabolism and lay the foundation for further investigation of efficient vaccines.

病毒作为专性细胞内寄生物，完全依赖宿主代谢系统并劫持宿主营养物质以完成自身复制。新城疫病毒（Newcastle disease virus, NDV）可引发急性高传染性禽类疾病，同时兼具溶瘤活性，能够在鸡源细胞与肿瘤细胞中高效复制。然而，目前对于NDV如何重编程宿主细胞代谢以实现高效复制的机制仍不明确。本团队此前通过转录组分析，在NDV感染过程中发现了谷氨酸转运蛋白基因溶质载体家族1成员3（solute carrier family 1 member 3, SLC1A3）的表达显著上调。为探究SLC1A3在NDV感染过程中的潜在功能，本研究首先通过p53与NF-κB通路，验证了NDV感染的DF-1及A549细胞中SLC1A3的显著上调表达。敲低SLC1A3的表达可抑制NDV的感染过程。蛋白质印迹（Western blot）分析进一步证实，谷氨酰胺而非谷氨酸、天冬酰胺或天冬氨酸是NDV复制所必需的营养物质。代谢流检测数据显示，NDV可促进谷氨酰胺分解进入三羧酸循环。值得注意的是，敲低SLC1A3的表达会降低谷氨酸水平与谷氨酰胺分解速率，这表明SLC1A3可通过推动谷氨酰胺分解以促进谷氨酸利用，进而助力宿主细胞内NDV的复制。综上，本研究数据表明SLC1A3是谷氨酰胺代谢的重要调控因子，并在NDV感染过程中被病毒劫持以实现高效复制。上述研究结果加深了我们对NDV与宿主细胞代谢相互作用的认知，并为后续高效疫苗的相关研究奠定了基础。