eIF4E3 drives translation of viral mRNAs with short 5’UTRs

Eukaryotic cells express three paralogs of the cap-binding protein eIF4E, yet the functions of the less-studied family members remain poorly understood. Here we demonstrate that eIF4E3, a paralog whose expression is tissue-restricted and whose activity is insensitive to inhibition by eIF4E-binding proteins (4EBPs), drives efficient translation of viral mRNAs with short 5’ untranslated regions (UTRs). Many negative-strand RNA viruses (NSVs), including vesicular stomatitis virus (VSV), respiratory syncytial virus (RSV), and influenza A virus (IAV), produce mRNAs with extremely short 5’UTRs that are incompatible with canonical cap-dependent scanning translation initiation. Using an auxin-inducible degron (AID) system to acutely deplete endogenous eukaryotic initiation factors during active viral infection, we demonstrate that translation of these short-UTR viral mRNAs occurs independently of eIF4E1, the canonical cap-binding protein, while remaining dependent on eIF4E3. In contrast, Ebola virus (EBOV), whose mRNAs bear long, structured 5’UTRs, remains eIF4E1-dependent, implicating 5’UTR length and structural complexity as cis determinants of eIF4E paralog selectivity. During VSV infection, 4EBP dephosphorylation sequesters eIF4E1 and broadly suppresses host cap-dependent translation. Because eIF4E3 escapes 4EBP-mediated regulation and preferentially engages short, unstructured 5’UTRs, it is uniquely positioned to sustain viral protein synthesis under these conditions. These findings reveal that VSV exploits a cellular paralog-switching mechanism by co-opting eIF4E3 to maintain viral translation when canonical eIF4F activity is suppressed and establish eIF4E3 as a proviral factor whose tissue-restricted expression in the lung may influence susceptibility to clinically important respiratory pathogens.