XPO1-dependent nuclear export regulates NS3 localization and promotes DENV-2 replication through mitochondrial remodeling and interferon suppression

Nucleocytoplasmic transport is essential for cellular homeostasis and is frequently exploited by viruses during infection. Although dengue virus (DENV) non-structural protein 3 (NS3) undergoes nuclear trafficking, the role of nuclear export pathways in its localization and in viral replication remains poorly understood. Here, we show that pharmacological inhibition of exportin 1 (XPO1) promotes the accumulation of DENV-2 NS3 in both the nucleus and mitochondria of infected Huh-7 cells. XPO1 inhibition also induces mitochondrial morphological alterations resembling those observed during DENV infection. Moreover, blockade of nuclear export enhances DENV-2 replication in interferon-stimulated cells by reducing type I interferon production, suggesting the establishment of a pro-viral cellular environment. Our findings reveal that XPO1-mediated nuclear export contributes to the regulation of NS3 localization and links nuclear export to mitochondrial remodeling and suppression of antiviral signaling during DENV infection.