Shutoff of Host Gene Expression in Influenza A Virus and Herpesviruses: Similar Mechanisms and Common Themes

Rivas, Hembly G.; Schmaling, Summer K.; Gaglia, Marta Maria

doi:10.3390/v8040102

Cited by 82 publications

(92 citation statements)

References 173 publications

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“…Given that transcription is not repressed in CrPV-3(R146A)-infected cells, we propose that CrPV-1A is responsible for host transcriptional shutoff during infection, which is consistent with recent reports that dicistrovirus infection results in inhibition of transcription (48,64). A large body of research suggests that inhibition of transcription is beneficial for viruses (72)(73)(74). Typically, this strategy is employed by viruses to inhibit antiviral responses triggered upon infection.…”

Section: Discussionsupporting

confidence: 89%

Disruption of Stress Granule Formation by the Multifunctional Cricket Paralysis Virus 1A Protein

Khong

Kerr

Yeung

et al. 2017

J Virol

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Stress granules (SGs) are cytosolic ribonucleoprotein aggregates that are induced during cellular stress. Several viruses modulate SG formation, suggesting that SGs have an impact on virus infection. However, the mechanisms and impact of modulating SG assembly in infected cells are not completely understood. In this study, we identify the dicistrovirus cricket paralysis virus 1A (CrPV-1A) protein that functions to inhibit SG assembly during infection. Moreover, besides inhibiting RNA interference, CrPV-1A also inhibits host transcription, which indirectly modulates SG assembly. Thus, CrPV-1A is a multifunctional protein. We identify a key R146A residue that is responsible for these effects, and mutant CrPV(R146A) virus infection is attenuated in Drosophila melanogaster S2 cells and adult fruit flies and results in increased SG formation. Treatment of CrPV(R146A)-infected cells with actinomycin D, which represses transcription, restores SG assembly suppression and viral yield. In summary, CrPV-1A modulates several cellular processes to generate a cellular environment that promotes viral translation and replication.IMPORTANCE RNA viruses encode a limited set of viral proteins to modulate an array of cellular processes in order to facilitate viral replication and inhibit antiviral defenses. In this study, we identified a viral protein, called CrPV-1A, within the dicistrovirus cricket paralysis virus that can inhibit host transcription, modulate viral translation, and block a cellular process called stress granule assembly. We also identified a specific amino acid within CrPV-1A that is important for these cellular processes and that mutant viruses containing mutations of CrPV-1A attenuate virus infection. We also demonstrate that the CrPV-1A protein can also modulate cellular processes in human cells, suggesting that the mode of action of CrPV-1A is conserved. We propose that CrPV-1A is a multifunctional, versatile protein that creates a cellular environment in virus-infected cells that permits productive virus infection.

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Section: Discussionsupporting

confidence: 89%

Disruption of Stress Granule Formation by the Multifunctional Cricket Paralysis Virus 1A Protein

Khong

Kerr

Yeung

et al. 2017

J Virol

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“…Viral RNases, like HSV vhs, Kaposi's sarcoma-associated herpesvirus (KSHV) ORF37 (SOX), murine herpesvirus 68 (MHV68) ORF37 (muSOX), and Epstein-Barr virus (EBV) ORF37 homolog (BGLF5), cleave mRNA into fragments. In a study exploring the patterns of RNA cleavage by the aforementioned DNA viral factors, it was determined that, in addition to evidence for global mRNA degradation (Rivas, Schmaling, and Gaglia, 2016), these viral RNases displayed preferential cleavage of RNA polymerase II-derived transcripts that contain a 7-methylguanosine 5’ cap and 3’ poly-adenylated tail (Gaglia et al, 2012). Through one of its RNA destabilizing mechanisms, vhs associates preferentially with the 5’ end of transcripts through the cap-binding protein complex, whereas the methods of mRNA targeting by SOX, muSOX, and BGLF5 await future characterization (Figure 2, left ).…”

Section: Antagonism Of Host Defense Gene Transcription By Multiplementioning

confidence: 99%

Diverse mechanisms evolved by DNA viruses to inhibit early host defenses

Crow

Lum

Sheng

et al. 2016

Critical Reviews in Biochemistry and Molecular Biology

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In mammalian cells, early defenses against infection by pathogens are mounted through a complex network of signaling pathways shepherded by immune-modulatory pattern-recognition receptors. As obligate parasites, the survival of viruses is dependent upon the evolutionary acquisition of mechanisms that tactfully dismantle and subvert the cellular intrinsic and innate immune responses. Here, we review the diverse mechanisms by which viruses that accommodate DNA genomes are able to circumvent activation of cellular immunity. We start by discussing viral manipulation of host defense protein levels by either transcriptional regulation or protein degradation. We next review viral strategies used to repurpose or inhibit these cellular immune factors by molecular hijacking or by regulating their post-translational modification status. Additionally, we explore the infection-induced temporal modulation of apoptosis to facilitate viral replication and spread. Lastly, the co-evolution of viruses with their hosts is highlighted by the acquisition of elegant mechanisms for suppressing host defenses via viral mimicry of host factors. In closing, we present a perspective on how characterizing these viral evasion tactics both broadens the understanding of virus-host interactions and reveals essential functions of the immune system at the molecular level. This knowledge is critical in understanding the sources of viral pathogenesis, as well as for the design of antiviral therapeutics and autoimmunity treatments.

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“…This 'host shutoff' phenotype can be triggered through a range of mechanisms that operate at nearly every stage of the gene expression cascade. Viruses whose host shutoff strategies involve the induction of widespread mRNA decay include the alpha and gammaherpesviruses, vaccinia virus (VACV), influenza A virus (IAV), and SARS coronavirus (SCoV) [1][2][3][4][5] In each of the above cases, mRNA degradation is induced via one or more internal endonucleolytic cleavages in the target mRNA or, in the case of VACV, direct removal of the mRNA 5' cap [5][6][7][8][9]. This is invariably followed by exonucleolytic degradation of the cleaved fragment(s) by components of the mammalian RNA decay machinery such as Xrn1 [1,10,11].…”

Section: Introductionmentioning

confidence: 99%

Nuclease escape elements protect messenger RNA against cleavage by multiple viral endonucleases

Muller

Glaunsinger

2017

Preprint

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During lytic Kaposi's sarcoma-associated herpesvirus (KSHV) infection, the viral endonuclease SOX promotes widespread degradation of cytoplasmic messenger RNA (mRNA). However, select mRNAs, including the transcript encoding interleukin-6 (IL-6), escape SOX-induced cleavage. IL-6 escape is mediated through a 3' UTR RNA regulatory element that overrides the SOX targeting mechanism. Here, we reveal that this protective RNA element functions to broadly restrict cleavage by a range of homologous and non-homologous viral endonucleases. However, it does not impede cleavage by cellular endonucleases. The IL-6 protective sequence may be representative of a larger class of nuclease escape elements, as we identified a similar protective element in the GADD45B mRNA. The IL-6 and GADD45B-derived elements display similarities in their sequence, putative structure, and several associated RNA binding proteins. However, the overall composition of their ribonucleoprotein complexes appears distinct, leading to differences in the breadth of nucleases restricted. These findings highlight how RNA elements can selectively control transcript abundance in the background of widespread virus-induced mRNA degradation.

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Shutoff of Host Gene Expression in Influenza A Virus and Herpesviruses: Similar Mechanisms and Common Themes

Cited by 82 publications

References 173 publications

Disruption of Stress Granule Formation by the Multifunctional Cricket Paralysis Virus 1A Protein

Disruption of Stress Granule Formation by the Multifunctional Cricket Paralysis Virus 1A Protein

Diverse mechanisms evolved by DNA viruses to inhibit early host defenses

Nuclease escape elements protect messenger RNA against cleavage by multiple viral endonucleases

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