Translational control during poxvirus infection

Focus Article

Nathan Meade, Stephen DiGiuseppe, Derek Walsh

Published Online: Oct 31 2018

DOI: 10.1002/wrna.1515

Full article on Wiley Online Library: HTML PDF

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Poxviruses are an unusual family of large double‐stranded (ds) DNA viruses that exhibit an incredible degree of self‐sufficiency and complexity in their replication and immune evasion strategies. Indeed, amongst their approximately 200 open reading frames (ORFs), poxviruses encode approximately 100 immunomodulatory proteins to counter host responses along with complete DNA synthesis, transcription, mRNA processing and cytoplasmic redox systems that enable them to replicate exclusively in the cytoplasm of infected cells. However, like all other viruses poxviruses do not encode ribosomes and therefore remain completely dependent on gaining access to the host translational machinery in order to synthesize viral proteins. Early studies of these intriguing viruses helped discover the mRNA cap and polyadenylated (polyA) tail that we now know to be present on most eukaryotic messages and which play fundamental roles in mRNA translation, while more recent studies have begun to reveal the remarkable lengths poxviruses go to in order to control both host and viral protein synthesis. Here, we discuss some of the central strategies used by poxviruses and the broader battle that ensues with the host cell to control the translation system, the outcome of which ultimately dictates the fate of infection. This article is categorized under: Translation > Translation Regulation

Overview of poxvirus infection and effects on translation. After poxvirus entry into the cytosol, transcriptionally competent viral cores begin to produce early viral mRNAs that are translated in the cytoplasm amongst the broader pool of host transcripts. Synthesis of early proteins leads to core uncoating and entry into the postreplicative stage. This involves the degradation of a large portion of host mRNAs along with the formation of viral factories (VFs). VFs are structurally complex and compartmentalized to facilitate many processes including DNA synthesis, transcription of intermediate and late gene products, viral protein synthesis and virion assembly. Notably, as VFs mature, cavities form that serve as the sub‐VF sites where late viral mRNAs accumulate together with ribosomes for translation (inset)

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Poxvirus factors that regulate translation during infection. Examples of poxvirus proteins that control various aspects of translation, as discussed in the main text. “?????” point to some interesting gaps in our current knowledge; how poxviruses activate ERK/p38MAPK signaling and the target (ribosomal or nonribosomal?) of the 169 protein that results in the formation of inactive 80S ribosomes in the cytoplasm remains unknown. Poxviruses such as vaccinia virus (VacV) encode a wide array of proteins that counter the function of protein kinase R (PKR) in phosphorylating eIF2α, which sequesters eIF2B and potently inhibits translation

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Translational control in the host cell. In response to mitogenic signaling, PI3K activates Akt that in turn inactivates the tuberous sclerosis complex (TSC1/2), a repressor of mTOR's GTPase, RHEB1. This activates mTORC1, containing Raptor, resulting in phosphorylation and inactivation of 4E‐BP1. mTORC2, containing Rictor, also activates Akt. Through complex pathways (dotted lines) that prevent a feedforward loop from forming, mTORC1 substrates such as p70S6K or Grb10 suppress mTORC2 and/or PI3K activity to control Akt. Once 4E‐BP1 has been inactivated, eIF4E is released to bind eIF4G and can be phosphorylated by the kinase, Mnk1 as part of the eIF4F complex. Through bridging interactions with eIF3, eIF4F recruits the 40S ribosome that is loaded with the eIF2‐tRNA^Met ternary complex. Once the AUG start codon is recognized, GTP hydrolysis and eIF2‐GDP release occurs in a manner facilitated by other eIFs (dotted lines). eIF2‐GDP is then recycled by eIF2B. Further details of these processes are provided in the main text

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