Inhibition of the FGFR4 signaling pathway had a reciprocal effect by dampening DENV replication and stimulating virus particle maturation, which is mediated, at least partly, by increasing prM cleavage. Similar results were obtained by inhibition of PI3K, arguing that the PI3K arm of the FGFR4 pathway confers this effect. Activation of the pathway by the natural ligand FGF19 or by overexpression of constitutive active FGFR4 mutants markedly reduced virus infectivity, thus confirming the specificity of the FGFR inhibitor treatment. We observed a reduction in FGFR4 protein abundance, together with a decrease in the phosphorylation levels of the adaptor protein FRS2α, at late time points after infection, whereas the amounts of the downstream kinase ERK1/2 were not affected. Therefore, we conclude that FGFR4 signaling is impaired during DENV infection specifically at the level of the membrane receptor but does not affect all kinases of this pathway.
Inhibition of the FGFR4 signaling pathway reduced DENV replication while promoting virus particle maturation, partially through enhanced prM cleavage. Comparable effects were observed with PI3K inhibition, suggesting the PI3K component of the FGFR4 pathway drives this response. Activation of the pathway via FGF19 or overexpression of constitutively active FGFR4 mutants significantly lowered virus infectivity, confirming the specificity of FGFR inhibitor effects. Late in infection, FGFR4 protein levels decreased, accompanied by reduced phosphorylation of the adaptor protein FRS2α, while downstream ERK1/2 kinase levels remained unchanged. These findings indicate that DENV infection specifically disrupts FGFR4 signaling at the receptor level without broadly affecting all kinases in the pathway.
Inhibition of the FGFR4 signaling pathway resulted in decreased DENV replication and increased maturation of virus particles, which is partly attributed to enhanced prM cleavage. Similar outcomes were noted with the inhibition of PI3K, indicating that the PI3K component of the FGFR4 pathway is responsible for this effect. Furthermore, activation of the pathway through the natural ligand FGF19 or by overexpressing constitutively active FGFR4 mutants significantly reduced virus infectivity, confirming the effect of the FGFR inhibitor. We observed a decrease in FGFR4 protein levels along with reduced phosphorylation of the adaptor protein FRS2α at later stages of infection, while the levels of the downstream kinase ERK1/2 remained unchanged. Thus, we conclude that FGFR4 signaling is diminished during DENV infection at the receptor level but does not impact all kinases within the pathway.
The inhibition of the FGFR4 signaling pathway led to reduced DENV replication and enhanced virus particle maturation, which is in part due to increased prM cleavage. Similar results were observed with PI3K inhibition, suggesting that this effect is mediated by the PI3K subunit of the FGFR4 pathway. In addition, pathway activation by the natural ligand FGF19 or constitutively active FGFR4 mutant overexpression markedly inhibited virus infectivity, demonstrating the activity of the FGFR inhibitor. We found that FGFR4 protein levels and phosphorylation of the adaptor protein FRS2 were decreased at late infection, whereas the downstream kinase ERK1/2 was not affected. Therefore, we conclude that FGFR4 signaling is reduced during DENV infection at the receptor level but not at all kinases in the pathway.
Inhibition of the FGFR4 signaling pathway led to reduced DENV replication and increased virus particle maturation, partially due to increased prM cleavage. Likewise, the inhibition of PI3K produced similar results, suggesting that the PI3K part of the FGFR4 pathway is the cause of this effect. Moreover, pathway activation by the natural ligand FGF19 or by overexpression of constitutively active FGFR4 mutants markedly decreased virus infectivity, validating the effect of the FGFR inhibitor. We found a reduction in FGFR4 protein expression and decreased phosphorylation of the adaptor protein FRS2α at later time points of infection, but the levels of the downstream kinase ERK1/2 were unchanged. Therefore, we conclude that FGFR4 signaling is reduced at the receptor level during DENV infection, but not all kinases in the pathway.