The Host DHX29 RNA Helicase Regulates HCMV Immediate Early Protein Synthesis

The dead box helicase DHX29 plays a critical role in the translation of mRNAs containing complex RNA secondary structure in their 5' untranslated regions. The human cytomegalovirus (HCMV) genome has a high GC content, suggesting the 5'UTRs of viral mRNAs may contain significant secondary structure and require DHX29 for their efficient translation initiation. We found that depleting DHX29 from primary human fibroblasts prior to infection reduced viral mRNA and protein levels and decreased HCMV replication. The defect in HCMV replication correlated with decreased expression of the HCMV immediate early proteins IE1 and IE2, which are necessary for the establishment of lytic infection. Analysis of polysome associated mRNAs revealed that the defect in IE1 and IE2 expression is due to decreased mRNA translation efficiency. We found that DHX29 depletion led to reduced levels of the eIF4F translation initiation complex, resulting from decreased translation of the eIF4G mRNA. However, in line with our previous results showing a minimal role for the eIF4F complex in HCMV mRNA translation, we found that depleting eIF4G prior to infection did not impact IE1 and IE2 translation. Together our results define a new role for DHX29 in regulating eIF4F-dependent translation and identify a critical role for DHX29 in the translation of HCMV mRNAs.

Expression of the HCMV immediate early proteins IE1 and IE2 is critical for the establishment of lytic replication and the reactivation of latent HCMV infections. Defining the mechanisms controlling HCMV IE1 and IE2 protein expression has the potential to identify new strategies for therapeutic interventions that can limit HCMV disease in immune naïve and immune compromised individuals. Our finding that the cellular DHX29 helicase is necessary for the efficient translation of mRNAs encoding IE1 and IE2 suggests that therapies that inhibit DHX29 could potentially be useful in treating HCMV disease and adds to the growing body of literature suggesting DHX29 activity is a disease driver in multiple indications including viral disease, inflammation and cancer.