Abstract
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/PGE2 signaling. Conversely, GCN2 overexpression/activation effectively contains DENV infection by inhibiting COX-2/PGE2 signaling. Mechanistically, deletion of GCN2 triggers enhanced production of COX-2/PGE2 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.
Highlights
Eukaryotic cells orchestrate innate defense mechanism of translational arrest in response to wide variety of cellular stresses, including heat shock, starvation, and viral infection [1]
We determined the viral yields in wild type (WT) and general control nonderepressible 2 kinase (GCN2)−/− mouse embryonic fibroblasts (MEFs) 3 days post dengue virus (DENV)-2 infection
As occurred with DENV-2, DENV-1 and 4 infection was largely enhanced in GCN2−/− MEFs as compared to WT MEFs (Figures S1A,B) confirming that cells lacking GCN2 are more susceptible to DENV infection
Summary
Eukaryotic cells orchestrate innate defense mechanism of translational arrest in response to wide variety of cellular stresses, including heat shock, starvation, and viral infection [1]. Four different intracellular kinases that are activated by a particular stress stimulus exist in eukaryotes such as general control nonderepressible 2 kinase (GCN2), activated during amino acid or serum starvation and UV stress [2], double stranded RNA dependent protein kinase (PKR), senses double stranded RNA [3], heme-regulated inhibitor (HRI), activated during heme deficiency and heat shock [4], while PKR-like endoplasmic reticulum kinase (PERK) is activated by unfolded protein response [5]. Though PKR is well-known for defense against variety of viral infections [7], the redundancy of PKR against various viruses exist [8], indicating the presence of other antiviral pathways. The implication of GCN2 pathway in Dengue pathogenesis has been poorly defined
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