Department of Biotechnology and Bioinformatics, School of Life-Sciences, University of Hyderabad, Hyderabad, India.
Laboratory of Molecular Cell Biology, Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India.
Front Immunol. 2020 Aug 13;11:1831. doi: 10.3389/fimmu.2020.01831. eCollection 2020.
Nutrient sensor GCN2 plays a crucial role in the maintenance of cellular homeostasis during the condition of amino acid deprivation. Dysfunction in the GCN2 signaling underlies several chronic metabolic diseases. Recent studies highlight the anti-viral potential of GCN2 against RNA viruses such as Sindbis and HIV. However, its effect on dengue virus (DENV) pathogenesis remains poorly understood. Herein, we report that GCN2 deficient cells show increased DENV replication and viral yield in the culture supernatants compared to WT cells infected with DENV. Notably, enhanced DENV replication in GCN2 cells is associated with increased COX-2/PGE signaling. Conversely, GCN2 overexpression/activation effectively contains DENV infection by inhibiting COX-2/PGE signaling. Mechanistically, deletion of GCN2 triggers enhanced production of COX-2/PGE through profound activation of Iκκ-NF-κB signaling pathway. Altogether our results unveil a hitherto unrecognized role of GCN2 in DENV pathogenesis, thereby suggesting that targeting the GCN2 pathway might offer a novel therapeutic intervention against DENV infection.
营养传感器 GCN2 在氨基酸缺乏条件下细胞内稳态的维持中起着至关重要的作用。GCN2 信号转导功能障碍是多种慢性代谢性疾病的基础。最近的研究强调了 GCN2 对辛德比斯病毒和 HIV 等 RNA 病毒的抗病毒潜力。然而，其对登革热病毒（DENV）发病机制的影响仍知之甚少。在此，我们报告称，与 WT 细胞相比，缺乏 GCN2 的细胞在感染 DENV 后培养上清液中的 DENV 复制和病毒产量增加。值得注意的是，GCN2 细胞中 DENV 复制的增强与 COX-2/PGE 信号的增加有关。相反，通过抑制 COX-2/PGE 信号转导，GCN2 的过表达/激活可有效控制 DENV 感染。从机制上讲，GCN2 的缺失通过 Iκκ-NF-κB 信号通路的深度激活触发 COX-2/PGE 的大量产生。总之，我们的研究结果揭示了 GCN2 在 DENV 发病机制中的一个以前未被识别的作用，提示靶向 GCN2 途径可能为 DENV 感染提供新的治疗干预。
