Dual role of Human antigen R in Dengue virus infection: suppression of replication and promotion of cap-independent translation

Abstract 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, in vivo validation in AG129 mice model highlights an inverse correlation between HuR expression and viral load and implicates 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. Author summary Understanding how Dengue virus interacts with human cells is key to finding better treatments. Our study looked at a human protein called HuR, which normally control the stability and the use of RNA inside our cells. We discovered that HuR has two important but opposite roles during dengue infection. Early on, it slows down the virus’s ability to make copies of its genetic material, helping to reduce infection. But later, when the virus struggles to use the normal method of making proteins, HuR steps in to help the virus make its proteins in a different way. This double-edged role of HuR shows how the virus cleverly uses host cell machinery at different stages of infection. Overall, this study uncovers the novel role of a specific RNA-binding protein of the host in orchestrating dengue virus infection and pathogenesis, highlighting its potential as a target for antiviral therapies. Competing Interest Statement The authors have declared no competing interest.