Modulation of the Translational Landscape During Herpesvirus Infection

Glaunsinger, Britt A.

doi:10.1146/annurev-virology-100114-054839

Cited by 23 publications

(25 citation statements)

References 123 publications

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“…Herpesviruses have double-stranded DNA (dsDNA) genomes and produce dsRNA as a by-product of their replication ( Jacquemont and Roizman, 1975 ) as detected in cells infected by herpes simplex virus (HSV) 1 ( Weber et al., 2006 ) and KSHV ( West et al., 2014 ). The double-stranded RNA-dependent protein kinase R (PKR) is a critical host cell factor in the recognition of virus-derived dsRNA (reviewed in Glaunsinger, 2015 ). Upon dsRNA recognition, PKR auto-phosphorylates, dimerizes, and subsequently phosphorylates eukaryotic translation initiation factor 2α(eIF2α), leading to inhibition of protein synthesis in virus-infected cells.…”

Section: Introductionmentioning

confidence: 99%

Quantitative Proteomics Analysis of Lytic KSHV Infection in Human Endothelial Cells Reveals Targets of Viral Immune Modulation

et al. 2020

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Summary Kaposi’s sarcoma herpesvirus (KSHV) is an oncogenic human virus and the leading cause of mortality in HIV infection. KSHV reactivation from latent- to lytic-stage infection initiates a cascade of viral gene expression. Here we show how these changes remodel the host cell proteome to enable viral replication. By undertaking a systematic and unbiased analysis of changes to the endothelial cell proteome following KSHV reactivation, we quantify >7,000 cellular proteins and 71 viral proteins and provide a temporal profile of protein changes during the course of lytic KSHV infection. Lytic KSHV induces >2-fold downregulation of 291 cellular proteins, including PKR, the key cellular sensor of double-stranded RNA. Despite the multiple episomes per cell, CRISPR-Cas9 efficiently targets KSHV genomes. A complementary KSHV genome-wide CRISPR genetic screen identifies K5 as the viral gene responsible for the downregulation of two KSHV targets, Nectin-2 and CD155, ligands of the NK cell DNAM-1 receptor.

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Section: Introductionmentioning

confidence: 99%

Quantitative Proteomics Analysis of Lytic KSHV Infection in Human Endothelial Cells Reveals Targets of Viral Immune Modulation

et al. 2020

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“…Assembly of eIF4F is regulated by eIF4E-binding proteins like 4E-BP1, which prevent the association of eIF4E and eIF4G. Under nutrient-rich conditions that support high levels of protein synthesis, 4E-BP1 is maintained in an inactive form by mTORC1-mediated phosphorylation (32–34). When mTORC1 activity is lost, hypophosphorylated 4E-BP1 binds eIF4E to limit translation initiation.…”

Section: Introductionmentioning

confidence: 99%

Kaposi’s Sarcoma-Associated Herpesvirus Lytic Replication Interferes with mTORC1 Regulation of Autophagy and Viral Protein Synthesis

Pringle

Robinson

McCormick

2019

J Virol

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All viruses require host cell machinery to synthesize viral proteins. A host cell protein complex known as mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of protein synthesis. Under nutrient-rich conditions, mTORC1 is active and promotes protein synthesis to meet cellular anabolic demands. Under nutrient-poor conditions or under stress, mTORC1 is rapidly inhibited, global protein synthesis is arrested, and a cellular catabolic process known as autophagy is activated. Kaposi’s sarcoma-associated herpesvirus (KSHV) stimulates mTORC1 activity and utilizes host machinery to synthesize viral proteins. However, we discovered that mTORC1 activity was largely dispensable for viral protein synthesis, genome replication, and the release of infectious progeny. Likewise, during lytic replication, mTORC1 was no longer able to control autophagy. These findings suggest that KSHV undermines mTORC1-dependent cellular processes during the lytic cycle to ensure efficient viral replication.

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“…The ability of PAA to enhance NanoLuc protein activity, with no commensurate change in RNA expression, suggests that viral late genes may have a possible role in tempering translation. Manipulation of host translational machinery by the herpesviruses is a common strategy that is required for optimal virus replication and the production of virus progeny (48).…”

Section: Discussionmentioning

confidence: 99%

Lytic infection with murine gammaherpesvirus 68 activates host and viral RNA polymerase III promoters and enhances non-coding RNA expression

Knox

Mueller

Medina

et al. 2019

Preprint

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218 words Importance: 141 words Text: 5,479 words γHV68 infection activates pol III-dependent promoters 2 ABSTRACT 1RNA polymerase III (pol III) transcribes multiple non-coding (nc) RNAs that are essential for cellular function. Pol 2 III-dependent transcription is also engaged during certain viral infections, including the gammaherpesviruses 3 (HVs), where pol III-dependent viral ncRNAs promote pathogenesis. Additionally, several host ncRNAs are 4 upregulated during HV infection and play integral roles in pathogenesis by facilitating viral establishment and 5 gene expression. Here we sought to investigate how pol III-dependent transcriptional activity was regulated 6 during gammaherpesvirus infection, using the murine gammaherpesvirus 68 (HV68) system. To compare the 7 transcriptional regulation of host and viral pol III-dependent ncRNAs, we analyzed a series of pol III-dependent 8 promoters using a newly-generated luciferase reporter optimized to measure pol III activity. We measured 9 promoter activity from these constructs at the translation level via luciferase activity and at the transcription level 10 via RT-qPCR. We further measured endogenous ncRNA expression at single cell-resolution by flow cytometry. 11These studies demonstrated that lytic infection with γHV68 increased the transcriptional activity of multiple host 12 and viral pol III-dependent promoters, and further identified the ability of accessory sequences to influence both 13 baseline and inducible promoter activity after infection. These studies highlight how lytic gammaherpesvirus 14 infection alters the transcriptional landscape of host cells to increase pol III-derived transcription, a process that 15 may further modify cellular function and enhance viral gene expression and pathogenesis. 16 IMPORTANCE 17Gammaherpesviruses are a prime example of how viruses can alter the host transcriptional landscape to 18 establish infection. Despite major insights into how these viruses modify RNA polymerase II-dependent 19 generation of messenger RNAs, how these viruses influence the activity of host RNA polymerase III remains 20 much less clear. Small non-coding RNAs produced by RNA polymerase III are increasingly recognized to play 21 critical regulatory roles in cell biology and virus infection. Studies of RNA polymerase III dependent transcription 22 are complicated by its use of multiple promoter types and diverse RNAs with variable stability and processing 23 requirements. Here, we established a reporter system to directly study RNA polymerase III-dependent promoter 24 responses during gammaherpesvirus infection and utilized single-cell flow cytometry-based methods to reveal 25 that gammaherpesvirus lytic replication broadly induces pol III activity to enhance host and viral non-coding RNA 26 expression within the infected cell. 27 γHV68 infection activates pol III-dependent promoters

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Modulation of the Translational Landscape During Herpesvirus Infection

Cited by 23 publications

References 123 publications

Quantitative Proteomics Analysis of Lytic KSHV Infection in Human Endothelial Cells Reveals Targets of Viral Immune Modulation

Quantitative Proteomics Analysis of Lytic KSHV Infection in Human Endothelial Cells Reveals Targets of Viral Immune Modulation

Kaposi’s Sarcoma-Associated Herpesvirus Lytic Replication Interferes with mTORC1 Regulation of Autophagy and Viral Protein Synthesis

Lytic infection with murine gammaherpesvirus 68 activates host and viral RNA polymerase III promoters and enhances non-coding RNA expression

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