The Influenza A Virus Endoribonuclease PA-X Usurps Host mRNA Processing Machinery to Limit Host Gene Expression

Gaucherand, Léa; Porter, Brittany K.; Levene, Rachel Emily; Price, Emma L.; Schmaling, Summer K.; Rycroft, Chris H.; Kevorkian, Yuzo; McCormick, Craig; Khaperskyy, Denys A.; Gaglia, Marta Maria

doi:10.1016/j.celrep.2019.03.063

Cited by 82 publications

(149 citation statements)

References 84 publications

(184 reference statements)

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“…PA-X shares its N-terminus with PA but has a unique 41 or 61 amino acid C-terminus 43, 47 . PA-X contributes to the shut-off of host protein synthesis by targeting host Pol II transcripts for destruction 48, 49 . Alignment of PA and PA-X proteins encoded by GFHK99 and MaMN99 viruses reveals 29 differences in PA and 9 differences in PA-X ( Supplementary Figure 6 ).…”

Section: Discussionmentioning

confidence: 99%

Collective interactions augment influenza A virus replication in a host-dependent manner

Phipps

Ganti

Jacobs

et al. 2019

Preprint

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22implicated the PA gene segment as a major driver of this phenotype and quantification of viral 33RNA synthesis indicated that both replication and transcription were affected. These findings 34 indicate that multiple distinct mechanisms underlie IAV reliance on multiple infection and 35 underscore the importance of virus-virus interactions in IAV infection, evolution and emergence. 36Importantly, multiple infection with identical viral genomes can also alter infection 58 outcomes. Such cooperation was documented for VSV and HIV, where rates of transcription and 59 replication were enhanced with increasing multiplicity of infection (MOI) 23,24 . Similarly, faster 60 kinetics of virus production were seen at high MOI for poliovirus and IAV 19,25 . In these instances, 61 it is thought that increased copy number of infecting viral genomes provides a kinetic benefit 62 important in the race to establish infection before innate antiviral responses take hold. Indeed, it 63 has been suggested that multiple infection may be particularly relevant for facilitating viral growth 64 under adverse conditions, such as antiviral drug treatment 3,26 . 65For IAV, an important adverse condition to consider is that of a novel host environment. 66IAVs occupy a broad host range, including multiple species of wild waterfowl, poultry, swine, 67 humans and other mammals 27,28 . Host barriers to infection typically confine a given lineage to 68 circulation in one species or a small number of related species 29,30 . Spillovers occur occasionally, 69 however, and can seed novel lineages. When a novel IAV lineage is established in humans, the 70 result is a pandemic of major public health consequence 31,32 . The likelihood of successful cross-71 species transfer of IAV is determined largely by the presence, absence, and compatibility of host 72 factors on which the virus relies to complete its life cycle, and on the viruses' ability to overcome 73 antiviral defenses in the novel host [33][34][35] . 74Our objective herein was to assess the degree to which IAV relies on the delivery of 75 multiple viral genomes to a cell to ensure production of progeny. In particular, we sought to 76 determine whether this phenotype varies with host species. We therefore examined the 77 multiplicity dependence of one human and a panel of avian-origin viruses in multiple host systems. 78Results from all virus/cell combinations tested confirm prior reports that cells multiply-infected with 79 IAV produce more viral progeny than singly-infected cells. Importantly, however, the extent to 80 which viral progeny production is concentrated within the multiply-infected fraction of a cell 81 population varies greatly with virus-host context. Two poultry-adapted H9N2 viruses (A/guinea 82 fowl/HK/WF10/99 (GFHK99) and A/quail/HK/A28945/88 (QaHK88)) exhibit an acute dependence 83 on multiple infection in mammalian systems that is greatly diminished in natural host systems. 84This strong dependence on multiple infection is not seen for the human strain, influenza 85 ...

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Section: Discussionmentioning

confidence: 99%

Collective interactions augment influenza A virus replication in a host-dependent manner

Phipps

Ganti

Jacobs

et al. 2019

Preprint

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“…Influenza viruses have caused fearful respiratory diseases and lead to 250 000–500 000 people's death every year . In general, influenza viruses can be categorized into three species: A, B, and C. Among them, the most virulent is influenza A viruses, which usually lead to fatal severe respiratory diseases . H7N9 virus (hemagglutinin7 gene and neuraminidase 9 gene) belongs to influenza A viruses, normally spreads among birds.…”

Section: Methodsmentioning

confidence: 99%

Carbon Nanodot–Based Fluorescent Method for Virus DNA Analysis with Isothermal Strand Displacement Amplification

Yang

Guo

Wang³

et al. 2019

Part & Part Syst Charact

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In this work, a fluorescent method is developed for ultrasensitive detection of virus DNA, coupling DNA‐modified carbon nanodots (CDs) and an isothermal amplification technology. The sensitivity is significantly improved with cyclic strand displacement polymerization and highly luminescent CDs. Taking the hemagglutinin7 (H7) gene and neuraminidase 9 (N9) gene as examples, the limits of detection are 4.6 × 10−15 and 3.4 × 10−15 m, respectively. Furthermore, the proposed method is highly selective and capable of detecting target sequences in biological samples, indicating great potential for applications in life science research and clinical diagnosis.

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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%

“…Editor: Andrew Mehle, University of Wisconsin Madison, UNITED STATES promiscuous than these results suggest and can select both for and against specific targets [12,13,[15][16][17][18][19][20].…”

mentioning

confidence: 96%

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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The Influenza A Virus Endoribonuclease PA-X Usurps Host mRNA Processing Machinery to Limit Host Gene Expression

Cited by 82 publications

References 84 publications

Collective interactions augment influenza A virus replication in a host-dependent manner

Collective interactions augment influenza A virus replication in a host-dependent manner

Carbon Nanodot–Based Fluorescent Method for Virus DNA Analysis with Isothermal Strand Displacement Amplification

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

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