Activation of host translational control pathways by a virus developmental switch
Regulation of gene expression at the level of mRNA translation is important for the control of numerous biological processes including cell growth, differentiation, development and the response to environmental stress. Unlike prokaryotes, the vast majority of eukaryotic mRNAs are unable to recognize ribosomes directly and rely instead on an intricate set of translation initiation factors that assemble a specialized multisubunit complex onto the mRNA 5′ terminus to recruit the 40S ribosome subunit. The responsiveness of individual constituents of this complex to a wide spectrum of cellular signals allows the translational machinery to respond rapidly to diverse physiological effectors. The 4E-BP translational repressor family, for example, sequesters eIF4E and prevents binding to eIF4G, limiting ribosome recruitment. Similarly, the ERK and p38-responsive eIF4G-associated kinase Mnk1 modulates eIF4E phosphorylation, which in specific instances has been associated with increased translation rates. Thus, regulated translation initiation factor complex assembly and modification is poised to potentiate important developmental decisions by controlling global and specific mRNA translation.
Viruses provide attractive models to study simple developmental decisions. In prokaryotes, much has been learned using bacteriophage λ to investigate how the lysis-lysogeny decision is made. In eukaryotes, latent herpesviruses exist in one of two developmental states within their hosts and must resolve an analogous question of whether to remain latent or initiate productive viral growth. Different herpesviruses permanently colonize distinct specialized host cell-types. Those that establish residency in dividing cell populations, exemplified by members of the γ-herpesvirus subfamily that includes Kaposi’s sarcoma associated herpesvirus (KSHV/HHV8), express a limited subset of viral genes that stimulate cell proliferation, allow for viral minichromosome replication and segregation, and evade antiviral defenses. In response to poorly understood environmental cues, these viruses can switch to a developmental program that results in productive replication. This alternate pathway involves activating a temporally coordinated cascade of viral lytic gene expression, which in turn results in massive viral DNA amplification, progeny virus production, and ultimately host cell destruction. To effectively switch its gene expression program, all herpesviruses produce a new population of viral mRNAs transcribed by the cellular RNA polymerase II, which are mostly capped and polyadenylated like their host counterparts, and these must successfully engage and reprogram the host cell translational apparatus. This is a critical component of the developmental switch because viruses are absolutely dependent upon the translational machinery resident in their hosts. Manipulating host translation initiation factors to ensure that nascent viral mRNAs successfully recruit ribosomes will therefore determine the overall level and efficacy with which the newly transcribed developmental instructions are executed. While we have a general understanding of how the viral transcriptome is altered for many viruses, a role for translational control in the developmental switch from a latent to a productively replicating state has not been described.
Kaposi’s sarcoma-associated herpesvirus (KSHV) is an important human pathogen and, like all herpesviruses, establishes a state of permanent residency in the infected host called latency. Major sites of KSHV latency are cells of the immune system and cells lining blood vessels. In individuals with weakened immunity, inappropriate growth of these cells driven by the resident virus can give rise to primary effusion lymphoma and Kaposi’s sarcoma, respectively. These life-threatening cancers are most common in patients with HIV/AIDS and have become a major source of mortality in parts of sub-Saharan Africa. Under appropriate stimuli, herpesviruses change their relationship with the host cell and begin to manufacture proteins required to assemble new infectious virus particles that can be released and spread. To achieve this, the virus hijacks key processes within the cell and conscripts them into producing viral proteins. A recent study describes for the first time how KSHV carefully manipulates the host protein synthesis machinery during the switch from latency to this specialized infectious virus production mode. The results show that although overall protein synthesis is diminished, key components of the host’s protein manufacturing machinery are actually stimulated, presumably to accelerate virus protein production.
Activation of Host Translational Control Pathways by a Viral Developmental Switch. PLoS Pathog 5(3): e1000334. doi:10.1371/journal.ppat.1000334
In response to numerous signals, latent herpesvirus genomes abruptly switch their developmental program, aborting stable host–cell colonization in favor of productive viral replication that ultimately destroys the cell. To achieve a rapid gene expression transition, newly minted capped, polyadenylated viral mRNAs must engage and reprogram the cellular translational apparatus. While transcriptional responses of viral genomes undergoing lytic reactivation have been amply documented, roles for cellular translational control pathways in enabling the latent-lytic switch have not been described. Using PEL-derived B-cells naturally infected with KSHV as a model, we define efficient reactivation conditions and demonstrate that reactivation substantially changes the protein synthesis profile. New polypeptide synthesis correlates with 4E-BP1 translational repressor inactivation, nuclear PABP accumulation, eIF4F assembly, and phosphorylation of the cap-binding protein eIF4E by Mnk1. Significantly, inhibiting Mnk1 reduces accumulation of the critical viral transactivator RTA through a post-transcriptional mechanism, limiting downstream lytic protein production, and impairs reactivation efficiency. Thus, herpesvirus reactivation from latency activates the host cap-dependent translation machinery, illustrating the importance of translational regulation in implementing new developmental instructions that drastically alter cell fate.
Related:
- Cellular Genes Targeted by KSHV MicroRNAs
- Modulation of the immune system by Kaposi’s sarcoma-associated herpesvirus
Tags: Biology, Herpes, KSHV, Medicine, Microbiology, Science, Virology, virus
