Human antigen R suppresses replication and promotes cap independent translation of Dengue viral RNA

Host RNA-binding proteins (RBPs) play a pivotal role in regulating dengue virus (DENV) translation and replication through interactions with untranslated regions (UTRs) of viral RNA. We investigated host proteins associated with detergent-resistant membranes (DRMs) of the DENV replication complex and identified Human antigen R (HuR) as a key RBP enriched in the DRM. HuR was found to negatively regulate DENV replication by binding the DENV-3′UTR and impeding the association of polypyrimidine tract-binding protein (PTB), a known RNA stabilizer. Additionally, infection-induced modulation of HuR stabilized host mRNAs involved in innate immunity. Interestingly, preliminary in vivo validation in the AG129 mouse model reveals an inverse correlation between HuR expression and viral load, implicating HuR in cytokine dysregulation. Notably, HuR promoted cap-independent translation of viral RNA during later stages of infection, when cap-dependent translation is suppressed. These findings reveal a dual role for HuR: restricting viral RNA replication while enhancing translation, highlighting its critical, phase-specific function in the DENV life cycle.