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Modulation of the Translational Landscape During Herpesvirus Infection - PubMed

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Modulation of the Translational Landscape During Herpesvirus Infection

Britt A Glaunsinger. Annu Rev Virol. 2015 Nov.

Abstract

Herpesviral mRNAs are produced and translated by cellular machinery, rendering them susceptible to the network of regulatory events that impact translation. In response, these viruses have evolved to infiltrate and hijack translational control pathways as well as to integrate specialized host translation strategies into their own repertoire. They are robust systems to dissect mechanisms of mammalian translational regulation and continue to offer insight into cis-acting mRNA features that impact assembly and activity of the translation apparatus. Here, I discuss recent advances revealing the extent to which the three herpesvirus subfamilies regulate both host and viral translation, thereby dramatically impacting the landscape of protein synthesis in infected cells.

Keywords: eIF4F; herpesvirus; protein kinase R; translation; uORF; unfolded protein response.

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Figures

Figure 1
Figure 1

Regulation of translation initiation complex assembly. (a) Initiation begins with loading of the eIF4F complex, comprising the eIF4E cap-binding protein, eIF4G scaffold, and eIF4A helicase, onto the cap. This leads to binding of the 40S ribosomal subunit in association with the initiation factors (eIF1, eIF1A, eIF3, eIF5, and eIF2 · GTP) that make up the 43S preinitiation complex, which is loaded with the charged initiator-methionine tRNA (Met). The 40S subunit then scans through the 5′ untranslated region of the mRNA until it reaches the start codon, whereupon the 60S ribosome joins and translation of the open reading frame begins. (b) Assembly of the eIF4F complex blocked by the interaction of eIF4E with unphosphorylated eIF4E-binding proteins (4E-BPs). This inhibitory interaction is prevented by the phosphorylation of 4E-BP by the mammalian target of rapamycin kinase complex 1 (mTORC1). In turn, mTORC1 is regulated by its inhibitor TSC2, which itself is inhibited upon phosphorylation by the kinase Akt.

Figure 2
Figure 2

Cellular stress response pathways that control translation. (a) Protein kinase R (PKR) is activated upon binding dsRNA and undergoes dimerization and autophosphorylation, which dramatically increases its kinase activity. It then phosphorylates eIF2α. Phosphorylated eIF2αbinds the guanine nucleotide exchange factor (GEF) eIF2B in a manner that blocks the GDP-to-GTP exchange required for translation initiation. The phosphatase PP1 inhibits eIF2αphosphorylation. (b) The unfolded protein response (UPR) is activated in response to endoplasmic reticulum (ER) stress. The ER-resident sensors IRE1, PERK, and ATF6 are held in an inactive state by the BiP chaperone. They are released upon ER stress, leading to translation inhibition and induction of transcription factors that induce UPR target genes.

Figure 3
Figure 3

Herpesvirus infection alters the global translational landscape of an infected cell. During herpes simplex virus 1 (HSV-1) and Kaposi’s sarcoma–associated herpesvirus (KSHV) infection the pool of mRNAs available for translation is significantly reduced due to mRNA degradation by the viral endonucleases vhs and SOX, respectively. In addition, vhs has the ability to stimulate translation of select mRNAs, such as those containing internal ribosome entry site (IRES) elements, in a manner independent of its mRNA degradation function. During human cytomegalovirus (HCMV) infection, translation is broadly impacted through increased abundance of multiple translation factors. This leads to both large-scale enhancement and repression of mRNAs associated with polysomes.

Figure 4
Figure 4

Controlling the rate of translation as a means to impact antigen processing and regulate viral gene expression. Many antigenic MHC I peptides are generated from rapidly degraded defective ribosomal products (DRiPs) made during translation. Viral proteins may avoid DRiP presentation by reducing their translation rate. The EBNA1 latency protein of Epstein-Barr virus contains a glycine-alanine repeat (GAr) domain that folds into G-quadruplex structures, which decrease EBNA1 translation and correlate with reduced antigen presentation. Viral protein translational efficiency can also be controlled by the presence of short upstream open reading frames (uORFs). (❶) uORFs decrease the translation rate of the primary ORF (1°ORF) by engaging scanning ribosomes, enabling only a subset to reinitiate at the downstream ORF. (❷) uORFs have also been shown to increase viral coding capacity by enabling ribosomes to bypass the 5′ primary ORF and reinitiate at a downstream internal ORF, rendering mRNAs functionally polycistronic. Rapidly degraded peptides produced from uORFs may also be a source of DRiPs.

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