Viral Immunology Lab, Molecular Biomedicine Department, BICS Unit. Margarita Salas Center for Biological Research (CIB-CSIC), Madrid, Spain.
Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Universitat de Barcelona (UB), Barcelona, Spain.
J Med Virol. 2024 Jul;96(7):e29752. doi: 10.1002/jmv.29752.
Antiviral signaling, immune response and cell metabolism are dysregulated by SARS-CoV-2, the causative agent of COVID-19. Here, we show that SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10 induce a significant mitochondrial and metabolic reprogramming in A549 lung epithelial cells. While ORF9b, ORF9c and ORF10 induced largely overlapping transcriptomes, ORF3a induced a distinct transcriptome, including the downregulation of numerous genes with critical roles in mitochondrial function and morphology. On the other hand, all four ORFs altered mitochondrial dynamics and function, but only ORF3a and ORF9c induced a marked alteration in mitochondrial cristae structure. Genome-Scale Metabolic Models identified both metabolic flux reprogramming features both shared across all accessory proteins and specific for each accessory protein. Notably, a downregulated amino acid metabolism was observed in ORF9b, ORF9c and ORF10, while an upregulated lipid metabolism was distinctly induced by ORF3a. These findings reveal metabolic dependencies and vulnerabilities prompted by SARS-CoV-2 accessory proteins that may be exploited to identify new targets for intervention.
SARS-CoV-2 是 COVID-19 的病原体，它会扰乱抗病毒信号、免疫反应和细胞代谢。在这里，我们表明 SARS-CoV-2 的辅助蛋白 ORF3a、ORF9b、ORF9c 和 ORF10 在 A549 肺上皮细胞中诱导显著的线粒体和代谢重编程。虽然 ORF9b、ORF9c 和 ORF10 诱导了大量重叠的转录组，但 ORF3a 诱导了一个不同的转录组，包括许多在线粒体功能和形态中具有关键作用的基因下调。另一方面，这四个 ORF 都改变了线粒体的动力学和功能，但只有 ORF3a 和 ORF9c 诱导了线粒体嵴结构的明显改变。基因组规模的代谢模型确定了所有辅助蛋白共享的代谢通量重编程特征和每个辅助蛋白特有的特征。值得注意的是，ORF9b、ORF9c 和 ORF10 中观察到氨基酸代谢下调，而 ORF3a 则明显诱导脂质代谢上调。这些发现揭示了 SARS-CoV-2 辅助蛋白引发的代谢依赖性和脆弱性，这可能被用来确定新的干预靶点。
