C19ORF66 Broadly Escapes Virus-Induced Endonuclease Cleavage and Restricts Kaposi’s Sarcoma-Associated Herpesvirus

Rodríguez, William J.; Srivastav, Kumaraman; Muller, Mandy

doi:10.1128/jvi.00373-19

Cited by 38 publications

(59 citation statements)

References 59 publications

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“…In particular, vhs -dependent transcriptional down-regulation contributes substantially to the reduction in total RNA levels for the respective genes (Fig Q in S2 File, Fig W in S2 File). Furthermore, a recent study identified a set of 74 genes that escape degradation by four herpesviral endonucleases, including vhs [51]. Almost all of these genes were excluded from our analysis due to low expression (87%), read-in transcription (7%) or proximity to nearby genes (3%).…”

Section: Discussionmentioning

confidence: 99%

Dissecting HSV-1-induced host shut-off at RNA level

Friedel

Whisnant

Djaković

et al. 2020

Preprint

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26Herpes simplex virus 1 (HSV-1) installs a profound host shut-off during lytic infection. 27 The virion host shut-off (vhs) protein plays a key role in this process by efficiently 28 cleaving both host and viral mRNAs in a translation-initiation-dependent manner. 29 Furthermore, the onset of viral DNA replication is accompanied by a rapid decline in 30 transcriptional activity of the host genome. Both mechanisms have tremendous impact 31 on the RNA expression profile of the infected cells. To dissect their relative 32 contributions and elucidate gene-specific host transcriptional responses throughout 33 the first 8h of lytic HSV-1 infection, we here employed RNA-seq of total, newly 34 transcribed (4sU-labelled) and chromatin-associated RNA in wild-type (WT) and vhs 35 infection of primary human fibroblasts. Following virus entry, vhs activity rapidly 36 plateaued at an elimination rate of around 30% of cellular mRNAs per hour until 8h p.i. 37In parallel, host transcriptional activity dropped down to 10-20%. While the combined 38 effects of both phenomena dominated infection-induced changes in total RNA, 39 extensive gene-specific transcriptional regulation was observable in chromatin-40 associated RNA. This was surprisingly concordant between WT HSV-1 and its vhs 41 mutant and at least in parts mediated by the embryonic transcription factor DUX4. 42 Furthermore, both WT and vhs infection induced strong transcriptional up-regulation 43 of a small subset of genes. Most of these were either poorly or not at all expressed 44 prior to infection but already primed by H3K4me3 histone marks at their promoters. 45 Most interestingly, analysis of chromatin-associated RNA revealed vhs-nuclease- 46 activity-dependent transcriptional down-regulation of at least 150 cellular genes, in 47 particular of many genes encoding integrin adhesome and extracellular matrix 48 components. This was accompanied by a vhs-dependent reduction in protein levels by 49 8h p.i. for many of these genes. In summary, our study provides a comprehensive 50 picture of the molecular mechanisms that govern cellular RNA metabolism during the 51 first 8h of lytic HSV-1 infection. 52 53 4 Author Summary 54The HSV-1 virion host shut-off (vhs) protein efficiently cleaves both host and viral 55 mRNAs in a translation-dependent manner. In this study, we model and quantify 56 changes in vhs activity as well as the virus-induced global loss of host transcriptional 57 activity during productive HSV-1 infection. In general, HSV-1-induced alterations in 58 total RNA levels were found to be predominantly shaped by these two global processes 59 rather than gene-specific regulation. In contrast, chromatin-associated RNA depicted 60 gene-specific transcriptional changes. This revealed highly concordant transcriptional 61 changes in WT and vhs infection, confirmed DUX4 as a key transcriptional regulator 62 in HSV-1 infection and depicted vhs-dependent, transcriptional down-regulation of the 63 integrin adhesome and extracellular matrix. The latt...

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Section: Discussionmentioning

confidence: 99%

Dissecting HSV-1-induced host shut-off at RNA level

Friedel

Whisnant

Djaković

et al. 2020

Preprint

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“…Depletion of host RNA decay factors is not sufficient to abrogate feedback between mRNA decay and Pol II occupancy muSOX expression alone is sufficient to reduce cytoplasmic populations of mRNA by 60-80% [28][29][30], and in this non-infectious setting the loss of promoter-proximal Pol II is dependent on the presence of the host RNA decay enzymes Xrn1 and Dis3L2 [25]. To determine if this mechanism is also sufficient to explain the loss of Pol II occupancy during MHV68 infection, we depleted Xrn1 and Dis3L2 individually or in tandem using siRNAs (Fig 2A).…”

Section: Accelerated Rna Decay Broadly Reduces Pol II Occupancymentioning

confidence: 99%

RNA decay during gammaherpesvirus infection reduces RNA polymerase II occupancy of host promoters but spares viral promoters

et al. 2020

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In mammalian cells, widespread acceleration of cytoplasmic mRNA degradation is linked to impaired RNA polymerase II (Pol II) transcription. This mRNA decay-induced transcriptional repression occurs during infection with gammaherpesviruses including Kaposi's sarcomaassociated herpesvirus (KSHV) and murine gammaherpesvirus 68 (MHV68), which encode an mRNA endonuclease that initiates widespread RNA decay. Here, we show that MHV68induced mRNA decay leads to a genome-wide reduction of Pol II occupancy at mammalian promoters. This reduced Pol II occupancy is accompanied by down-regulation of multiple Pol II subunits and TFIIB in the nucleus of infected cells, as revealed by mass spectrometrybased global measurements of protein abundance. Viral genes, despite the fact that they require Pol II for transcription, escape transcriptional repression. Protection is not governed by viral promoter sequences; instead, location on the viral genome is both necessary and sufficient to escape the transcriptional repression effects of mRNA decay. We propose a model in which the ability to escape from transcriptional repression is linked to the localization of viral DNA within replication compartments, providing a means for these viruses to counteract decay-induced transcript loss. Author summaryWhile transcription and messenger RNA (mRNA) decay are often considered to be the unlinked beginning and end of gene expression, recent data indicate that alterations to either stage can impact the other. Here we study this connection in the context of lytic gammaherpesvirus infection, which accelerates mRNA degradation through the expression of the viral endonuclease muSOX. We show that RNA polymerase II promoter occupancy is broadly reduced across mammalian promoters in response to infection-induced mRNA PLOS Pathogens | https://doi.

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“…All host shutoff RNases cause global decreases in host mRNA abundance, revealed by transcriptome-wide studies [13][14][15], and display a preference for mRNAs while sparing housekeeping noncoding RNAs (ncRNAs) [12,16,17]. However, host shutoff RNases are less PLOS PATHOGENS PLOS Pathogens | https://doi.…”

Section: Selection Of Targeted and Protected Rnas And Protein/proteinmentioning

confidence: 99%

“…HSV vhs is thought to cleave most RNAs close to the 5 0 cap, with the exception of stress response mRNAs with adenylate/uridylate (AU)-rich elements in their 3 0 untranslated region (UTR), which vhs cleaves near the AU-rich element and whose 5 0 portion remains stable [28,29]. Additional complexity to the SOX targeting mechanism was revealed by the identification of SOX-resistant, or "escapee" mRNAs, which contain a structured RNA element, the "SOX resistance element" (SRE), in the 3 0 UTR [15,30,31]. The SRE recruits several host RNA binding proteins that inhibit SOX-mediated cleavage through an unknown mechanism ( Fig 1C) [30][31][32].…”

Section: Plos Pathogensmentioning

confidence: 99%

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Fine-tuning a blunt tool: Regulation of viral host shutoff RNases

2020

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The evolutionary arms race between host and pathogen has resulted in the ability of many human viruses to alter the host gene expression profile during infection, in order to redirect cellular resources towards viral gene expression and inhibit cell-intrinsic host immune responses. In particular, multiple viruses globally reduce host gene expression in a process termed "host shutoff." Multiple mechanisms of host shutoff exist, including translational and transcriptional shutoff, but several viruses carry out host shutoff by encoding ribonucleases (RNases) that degrade host messenger RNAs (mRNAs). Viral host shutoff RNases include the influenza A virus polymerase acidic-X (PA-X) [1], the herpes simplex viruses (HSV-1 and -2) virion host shutoff protein (vhs) [2], and the Kaposi's sarcoma-associated herpesvirus (KSHV) shutoff and exonuclease (SOX) protein [3] and its homologs, muSOX from murine gammaherpesvirus 68 (MHV68) [4] and BGLF5 from Epstein-Barr virus (EBV) [5]. These RNases contribute to efficient formation of virions and/or reduction of innate immune signaling [6][7][8]. For example, in the absence of EBV BGLF5, the virus produces fewer mature capsids, many of which remain trapped in the nucleus [7]. Vhs-deficient HSV replicates well in many common tissue culture models [9] but shows replication defects in relevant cell types, such as cerebellar granule neurons [8]. Moreover, in mice, viruses lacking detectable host shutoff activity replicate to lower viral titers in neuronal tissue [9], indicating a restriction of viral replication probably related to host immune responses. Influenza A virus PA-X also limits host antiviral and proinflammatory responses in several animal models [1,10,11] but has minimal effect on viral replication both in vivo and in cell culture [1,11,12]. Although host shutoff RNases are important for successful viral infection, their activity presents an interesting problem for the viruses that encode them. Unregulated RNase activity could degrade viral RNAs or host mRNAs encoding proteins that the virus needs. Moreover, drastic depletion of the mRNA pool by the virus could trigger antiviral host stress responses and cell death. It is thus unsurprising that evidence is now emerging that viruses posttranslationally regulate the activity of their host shutoff RNases through a variety of mechanisms, reviewed herein (Fig 1), to finetune host gene regulation without inhibiting viral replication. Selection of targeted and protected RNAs and protein/protein interactionsAll host shutoff RNases cause global decreases in host mRNA abundance, revealed by transcriptome-wide studies [13][14][15], and display a preference for mRNAs while sparing housekeeping noncoding RNAs (ncRNAs) [12,16,17]. However, host shutoff RNases are less PLOS PATHOGENS PLOS Pathogens | https://doi.

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C19ORF66 Broadly Escapes Virus-Induced Endonuclease Cleavage and Restricts Kaposi’s Sarcoma-Associated Herpesvirus

Cited by 38 publications

References 59 publications

Dissecting HSV-1-induced host shut-off at RNA level

Dissecting HSV-1-induced host shut-off at RNA level

RNA decay during gammaherpesvirus infection reduces RNA polymerase II occupancy of host promoters but spares viral promoters

Fine-tuning a blunt tool: Regulation of viral host shutoff RNases

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