A Herpesviral Immediate Early Protein Promotes Transcription Elongation of Viral Transcripts

Fox, Hannah L.; Dembowski, Jill A.; DeLuca, Neal A.

doi:10.1128/mbio.00745-17

Cited by 56 publications

(85 citation statements)

References 71 publications

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“…3c), showed strong positive correlations with viral transcripts. Similarly, we found that RASD1 and RRAD were up-regulated in previously published microarray, RNA-seq, and ribosome profiling datasets [5,6,30,31], indicating that the induction of these two genes is independent of the cell type and virus strain. To investigate the influence of RASD1 and RRAD on viral production, we depleted RASD1 and RRAD by siRNA knockdown prior to infection ( Fig.…”

Section: The Small Gtpases Rasd1 and Rrad Are Expressed In Infected Csupporting

confidence: 77%

Single-cell RNA-sequencing of Herpes simplex virus 1-infected cells identifies NRF2 activation as an antiviral program

Wyler

Franke

Menegatti

et al. 2019

Preprint

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AbstractHerpesvirus infection initiates a range of perturbations in the host cell, which remain poorly understood at the level of individual cells. Here, we quantified the transcrips of single human primary fibroblasts during the first hours of lytic infection with HSV-1. By applying a generalizable analysis scheme, we defined a precise temporal order of early viral gene expression and found unexpected bifurcations and bottlenecks. We identified individual host cell genes and pathways relevant in early infection by combining three different computational approaches: gene and pathway overdispersion analysis, prediction of cell-state transition probabilities as well as future cell states. One transcriptional program, which was turned on in infected cells and correlated with increased resistance to infection, implicated the transcription factor NRF2. Consequently, Bardoxolone methyl, a known NRF2 agonist, impaired virus production, suggesting that NRF2 activation restricts the progression of viral infection. Our study provides novel insights into early stages of HSV-1 infection and serves as a general blueprint for the investigation of heterogenous cell states in virus infection.

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Section: The Small Gtpases Rasd1 and Rrad Are Expressed In Infected Csupporting

confidence: 77%

Single-cell RNA-sequencing of Herpes simplex virus 1-infected cells identifies NRF2 activation as an antiviral program

Wyler

Franke

Menegatti

et al. 2019

Preprint

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“…A number of viral proteins that facilitate viral transcription are known to localize to VRCs. For example, these include HSV-1, ICP0, infected-cell proteins 4 (ICP4), 22 (ICP22), and 27 (ICP27), and products of the CMV UL112-113 gene [11,15,64,[149][150][151]. The localization of viral proteins that facilitate both DNA replication and transcription, as is the case for polyomavirus large T antigen and papillomavirus E2 and E3 proteins, further support a case for VRCs as sites of both viral DNA replication and transcription [11,55,[137][138][139][140]152,153].…”

Section: Transcriptionmentioning

confidence: 85%

Replication Compartments of DNA Viruses in the Nucleus: Location, Location, Location

Charman

Weitzman

2020

Viruses

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DNA viruses that replicate in the nucleus encompass a range of ubiquitous and clinically important viruses, from acute pathogens to persistent tumor viruses. These viruses must co-opt nuclear processes for the benefit of the virus, whilst evading host processes that would otherwise attenuate viral replication. Accordingly, DNA viruses induce the formation of membraneless assemblies termed viral replication compartments (VRCs). These compartments facilitate the spatial organization of viral processes and regulate virus-host interactions. Here, we review advances in our understanding of VRCs. We cover their initiation and formation, their function as the sites of viral processes, and aspects of their composition and organization. In doing so, we highlight ongoing and emerging areas of research highly pertinent to our understanding of nuclear-replicating DNA viruses.Viruses 2020, 12, 151 2 of 20 The Initiation and Formation of Replication CompartmentsDNA viruses that replicate in the nucleus exhibit a diverse array of strategies to complete their replication cycle and ultimately produce progeny virions. Despite their many differences, the strategies employed by DNA viruses to initiate productive infection and establish VRCs share many features in common. Indeed, it is likely that all DNA viruses that replicate in the nucleus form VRCs. Following penetration of the host cell and the transport of viral capsids/cores, viral DNA genomes enter the nucleus, where they begin a program of temporally regulated gene expression that initiates productive infection [1,2]. Early gene products include viral proteins required to manipulate the host-cell environment and replicate the viral genome. Viral replication proteins interact with the viral genome and initiate genome replication leading to VRC formation, which is often in concert with certain co-opted host proteins. However, these viruses must overcome several challenges to form VRCs successfully. Firstly, incoming genomes must avoid cellular intrinsic antiviral defenses and homeostatic regulatory pathways such as elements of the DNA damage response (DDR) that respond to the presence of foreign DNA and act to suppress viral gene expression [3][4][5][6][7][8][9][10]. Secondly, VRCs typically form at specific sites within the nucleus, suggesting that viral genomes need to be targeted to these sites in order to initiate VRC formation [6,11,12]. Furthermore, it has been hypothesized that the formation and growth of VRCs may require manipulation of the nuclear environment and the re-organization of host chromatin to overcome the spatial restraints of the nucleus [11][12][13][14][15]. In this section, we review key features of VRC initiation and highlight some major challenges to VRC formation. Interplay between Viral Replication Compartment Formation and Promyelocytic Leukemia Protein Nuclear BodiesA common theme amongst many nuclear-replicating DNA viruses is initiation of VRCs at sites in close proximity to promyelocytic leukemia protein (PML) nuclear bodies (NBs). Since the dis...

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“…220Furthermore, the IE gene product ICP22 is required for the recruitment of SSRP1 to viral 221 DNA(Fox et al, 2017). To verify the timing of recruitment of Mediator to viral DNA, we co-222 stained infected cells for infecting viral genomes and the Mediator component Med23 (Figure 223…”

mentioning

confidence: 99%

Temporal Viral Genome-Protein Interactions Define Distinct Stages of Productive Herpesviral Infection

Dembowski

DeLuca

2018

Preprint

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29Herpesviruses utilize multiple mechanisms to redirect host proteins for use in viral 30 processes and to avoid recognition and repression by the host. To investigate the dynamic 31 interactions between HSV-1 DNA and viral and host proteins, we developed an approach to 32 identify proteins that associate with the infecting viral genome from nuclear entry through 33 packaging. We found that input viral DNA progressed within six hours through four temporal 34 stages where the genomes: 1. interacted with intrinsic and DNA damage response proteins, 35 2. underwent a robust transcriptional switch mediated largely by ICP4, 3. engaged in 36 replication, repair, and continued transcription, and then 4. transitioned to a more 37 transcriptionally inert state engaging de novo synthesized viral structural components while 38 maintaining interactions with replication proteins. Using a combination of genetic, imaging, 39 and proteomic approaches, we provide a new and temporally compressed view of the HSV-1 40 life cycle based on genome-proteome dynamics. 41 42 43

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A Herpesviral Immediate Early Protein Promotes Transcription Elongation of Viral Transcripts

Cited by 56 publications

References 71 publications

Single-cell RNA-sequencing of Herpes simplex virus 1-infected cells identifies NRF2 activation as an antiviral program

Single-cell RNA-sequencing of Herpes simplex virus 1-infected cells identifies NRF2 activation as an antiviral program

Replication Compartments of DNA Viruses in the Nucleus: Location, Location, Location

Temporal Viral Genome-Protein Interactions Define Distinct Stages of Productive Herpesviral Infection

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