The DNA damage response (DDR) maintains genomic integrity through an elaborate network of signaling pathways that sense DNA damage and recruit effector factors to repair damaged DNA. DDR signaling pathways are usurped and manipulated by the replication programs of many viruses. Here, we review the papillomavirus (PV) life cycle, highlighting current knowledge of how PVs recruit and engage the DDR to facilitate productive infection.
By commandeering cellular translation initiation factors, or destroying those dispensable for viral mRNA translation, viruses often suppress host protein synthesis. In contrast, cellular protein synthesis proceeds in human cytomegalovirus (HCMV)-infected cells, forcing viral and cellular mRNAs to compete for limiting translation initiation factors. Curiously, inactivating the host translational repressor 4E-BP1 in HCMV-infected cells stimulates synthesis of the cellular poly(A) binding protein (PABP), significantly increasing PABP abundance. Here, we establish that new PABP synthesis is translationally controlled by the HCMV-encoded UL38 mammalian target of rapamycin complex 1-activator. The 5′ UTR within the mRNA encoding PABP contains a terminal oligopyrimidine (TOP) element found in mRNAs, the translation of which is stimulated in response to mitogenic, growth, and nutritional stimuli, and proteins encoded by TOP-containing mRNAs accumulated in HCMV-infected cells. Furthermore, UL38 expression was necessary and sufficient to regulate expression of a PABP TOP-containing reporter. Remarkably, preventing the rise in PABP abundance by RNAi impaired eIF4E binding to eIF4G, thereby reducing assembly of the multisubunit initiation factor eIF4F, viral protein production, and replication. This finding demonstrates that viruses can increase host translation initiation factor concentration to foster their replication and defines a unique mechanism whereby control of PABP abundance regulates eIF4F assembly.
Irrespective of their effects on ongoing host protein synthesis, productive replication of the representative alphaherpesvirus herpes simplex virus type 1, the representative gammaherpesvirus Kaposi's sarcoma herpesvirus, and the representative betaherpesvirus human cytomegalovirus [HCMV] stimulates the assembly of the multisubunit, cap-binding translation factor eIF4F. However, only HCMV replication is associated with an increased abundance of eIF4F core components (eIF4E, eIF4G, eIF4A) and the eIF4F-associated factor poly(A) binding protein (PABP). Here, we demonstrate that the increase in translation factor concentration was readily detected in an asynchronous population of HCMV-infected primary human fibroblasts, abolished by prior UV inactivation of virus, and genetically dependent upon viral immediate-early genes. Strikingly, while increased mRNA steady-state levels accompanied the rise in eIF4E and eIF4G protein levels, the overall abundance of PABP mRNA, together with the half-life of the polypeptide it encodes, remained relatively unchanged by HCMV infection. Instead, HCMV-induced PABP accumulation resulted from new protein synthesis and was sensitive to the mTORC1-selective inhibitor rapamycin, which interferes with phosphorylation of the mTORC1 substrate p70 S6K and the translational repressor 4E-BP1. While virus-induced PABP accumulation did not require p70 S6K, it was inhibited by the expression of a dominant-acting 4E-BP1 variant unable to be inactivated by mTORC1. Finally, unlike the situation in alpha-or gammaherpesvirus-infected cells, where PABP is redistributed to nuclei, PABP accumulated in the cytoplasm of HCMV-infected cells. Thus, cytoplasmic PABP accumulation is translationally controlled in HCMV-infected cells via a mechanism requiring mTORC1-mediated inhibition of the cellular 4E-BP1 translational repressor.Herpesvirus mRNAs contain methyl-7-GTP caps and 3Ј polyadenylate tails like their host cell counterparts and are primarily translated by a cap-dependent mechanism. Assembly of the cap-binding protein eIF4E, eIF4G, and the RNA helicase eIF4A into the active, cap-binding, multisubunit translation initiation factor eIF4F represents a key step regulating translation (reviewed in reference 33). In addition to controlling small ribosome subunit recruitment to the mRNA 5Ј end, whereupon a scanning mechanism commences to locate the initiator AUG codon, eIF4F assembly is responsive to a diverse assortment of cell stress and signaling inputs, including viral infection (24). Typically, eIF4E is bound to the translational repressor 4E-BP1. Hyperphosphorylation of 4E-BP1 by activated mTORC1 relieves this repression, releasing eIF4E and exposing the binding site for eIF4G, a large assembly platform bound to eIF4A. eIF4G also binds eIF3, which directly associates with the 40S ribosome subunit. The cellular poly(A) binding protein (PABP) and the eIF4E kinase Mnk are eIF4F-associated proteins that physically associate with eIF4G and act to stimulate translation. Bound to both the 3Ј poly(A) tail and...
SUMMARY Unlike many viruses that suppress cellular protein synthesis, host mRNA translation and polyribosome formation are stimulated by human cytomegalovirus (HCMV). How HCMV impacts the translationally-regulated cellular mRNA repertoire and its contribution to virus biology remains unknown. We show using polysome profiling that HCMV presides over the cellular translational landscape, selectively accessing the host genome to extend its own coding capacity and regulate virus replication. Expression of the HCMV UL38 mTORC1-activator partially recapitulates these translational alterations in uninfected cells. The signature of cellular mRNAs translationally-stimulated by HCMV resembles pathophysiological states where translation initiation factor levels or activity increase such as cancer. In contrast, cellular mRNAs repressed by HCMV include those involved in differentiation and the immune response. Surprisingly, interfering with the virus-induced activation of cellular mRNA translation can either limit or enhance HCMV growth. The unanticipated extent to which HCMV specifically manipulates host mRNA translation may aid in understanding its association with complex inflammatory disorders and cancer.
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