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Review
. 2016 Apr 16;8(4):102.
doi: 10.3390/v8040102.

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

Hembly G Rivas  1   2 , Summer K Schmaling  3 , Marta M Gaglia  4   5
Affiliations
Review

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

Hembly G Rivas et al. Viruses. .

Abstract

The ability to shut off host gene expression is a shared feature of many viral infections, and it is thought to promote viral replication by freeing host cell machinery and blocking immune responses. Despite the molecular differences between viruses, an emerging theme in the study of host shutoff is that divergent viruses use similar mechanisms to enact host shutoff. Moreover, even viruses that encode few proteins often have multiple mechanisms to affect host gene expression, and we are only starting to understand how these mechanisms are integrated. In this review we discuss the multiplicity of host shutoff mechanisms used by the orthomyxovirus influenza A virus and members of the alpha- and gamma-herpesvirus subfamilies. We highlight the surprising similarities in their mechanisms of host shutoff and discuss how the different mechanisms they use may play a coordinated role in gene regulation.

Keywords: Kaposi’s sarcoma-associated herpesvirus; RNA degradation; herpes simplex virus; herpesviruses; host shutoff; influenza A virus; transcription block.

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Figures

Figure 1
Figure 1
Herpesviruses and influenza A virus use multiple mechanisms to block host gene expression. In eukaryotes, production of proteins requires transcription, processing, nuclear export, and translation of mRNAs. The α-herpesvirus herpes simplex viruses (HSV), the γ-herpesviruses, and influenza A virus (IAV) use multiple viral factors to negatively regulate different stages of mRNA biogenesis and reduce host gene expression. They also stimulate host mRNA degradation.
Figure 2
Figure 2
RNA degradation by herpesviral and IAV RNases and its downstream consequences. Viral host shutoff RNases cut mRNAs internally (a), leading to fragment degradation by cellular exonucleases (b). The location of the cut sites differs depending on the RNase ((c), inset). IAV PA-X also differs by potentially associating with targets in the nucleus (d). Secondary consequences of the RNA degradation include: (e) association of PABPC with importins and nuclear accumulation of PABPC, which results in mRNA hyperadenylation and export block (f); (g) a feedback inhibition of transcription mediated by the cellular exonucleases; (h) inhibition of formation of cytoplasmic stress granules.
Figure 3
Figure 3
HSV ICP27 and IAV NS1 block mRNA processing. Newly transcribed pre-mRNAs are processed by splicing, that is the removal of introns (in yellow) through the action of the spliceosome complex. HSV ICP27 blocks the first step of complex assembly at splice sites. The pre-mRNAs are also processed at their 3′ end by the cleavage and polyadenylation complex (CPSF), which cleaves the RNA downstream of the polyadenylation signal (PAS) and allows poly(A) polymerase (PAP) to add short poly(A) tails. Nuclear PABPN is then required for stimulation of processive PAP activity and addition of the full-length poly(A) tails. IAV NS1 interferes with both steps of the process. For simplicity, splicing and 3′ end processing are represented in sequence, but they may occur simultaneously and also in part co-transcriptionally. IAV NS1 also interacts with components of the nuclear mRNA export complex (NXF1, p15, Rae1 and E1B-AP5) and blocks mRNA export.
Figure 4
Figure 4
Both HSV-1 and IAV block host transcription. Transcription by RNA polymerase II (Pol II) consists of multiple steps: recruitment to the DNA, initiation, mediated by phosphorylation of the serine 5 (Ser5) of the C-terminal domain (CTD) of the large subunit of the Pol II complex by TFIIH, and elongation, mediated by phosphorylation of Ser2 of the CTD by cyclin-dependent kinase 9 (CDK9). Both ICP27 and the IAV RNA-dependent RNA polymerase cause ubiquitination (Ub) and proteasome-mediated degradation of Pol II, but may associate with different phosphorylated forms of the complex. HSV also blocks Pol II recruitment to the DNA via unknown factors and CDK9 activity via ICP22.
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References

    1. Dauber B., Saffran H.A., Smiley J.R. The herpes simplex virus 1 virion host shutoff protein enhances translation of viral late mRNAs by preventing mRNA overload. J. Virol. 2014;88:9624–9632. doi: 10.1128/JVI.01350-14. - DOI - PMC - PubMed
    1. Khaperskyy D.A., Schmaling S., Larkins-Ford J., McCormick C., Gaglia M.M. Selective degradation of host RNA polymerase II transcripts by influenza A virus PA-X host shutoff protein. PLoS Pathog. 2016;12:102. doi: 10.1371/journal.ppat.1005427. - DOI - PMC - PubMed
    1. Wu J., Chen Z.J. Innate immune sensing and signaling of cytosolic nucleic acids. Annu. Rev. Immunol. 2014;32:461–488. doi: 10.1146/annurev-immunol-032713-120156. - DOI - PubMed
    1. De Weerd N.A., Nguyen T. The interferons and their receptors—Distribution and regulation. Immunol. Cell Biol. 2012;90:483–491. doi: 10.1038/icb.2012.9. - DOI - PMC - PubMed
    1. Haller O., Kochs G., Weber F. The interferon response circuit: Induction and suppression by pathogenic viruses. Virology. 2006;344:119–130. doi: 10.1016/j.virol.2005.09.024. - DOI - PMC - PubMed

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