Lost in translation: interferon-stimulated genes targeting flavivirus protein synthesis

Flaviviruses are positive-sense RNA viruses that rely entirely on host translation machinery to express their genome, making protein synthesis a central point of vulnerability. Interferon-stimulated genes (ISGs) exploit this dependence through diverse and mechanistically distinct strategies. PKR and IFIT proteins interfere primarily with translation initiation by targeting initiation factors or cap recognition, whereas SLFN11 and SAMD9L impair elongation through codon- and tRNA-dependent mechanisms. In parallel, ZAP, SHFL, and ISG20 inhibit translation by excluding viral RNAs from ribosomes or promoting their degradation. These antiviral activities highlight that ISG-mediated restriction is often highly selective, targeting viral RNAs on features such as cap structure, nucleotide composition, codon usage, and RNA folding. As a result, translation emerges as a central interface of host-virus conflict, where subtle differences between viral and cellular mRNAs can be exploited to achieve potent antiviral effects while preserving host protein synthesis. This minireview highlights recent advances in the identification and characterization of ISGs that restrict flavivirus protein synthesis and integrates them into a unified framework based on their primary mechanism of action. Emphasizing how host defenses target multiple stages of translation provides a conceptual basis for understanding how innate immunity controls flavivirus replication and highlights viral translation as a promising target for selective antiviral strategies.