The influenza A virus endoribonuclease PA-X usurps host mRNA processing machinery to limit host gene expression

Gaucherand, Léa; Porter, Brittany K.; Schmaling, Summer K.; Rycroft, Chris H.; Kevorkian, Yuzo; McCormick, Craig; Khaperskyy, Denys A.; Gaglia, Marta Maria

doi:10.1101/442996

Cited by 13 publications

(31 citation statements)

References 68 publications

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“…While nsp1 specifically targets RNA polymerase II-transcribed RNAs in cells (195), the spectrum of mRNAs that are cleaved in response to nsp1 is unclear. However, if it functions analogously to mRNA-targeting host shutoff factors in other viruses, host transcripts may be broadly downregulated (198)(199)(200).…”

Section: Host Shutoffmentioning

confidence: 99%

The molecular virology of coronaviruses

Hartenian

Nandakumar

Lari

et al. 2020

Journal of Biological Chemistry

423

548

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Few human pathogens have been the focus of as much concentrated worldwide attention as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2), the cause of COVID-19. Its emergence into the human population and ensuing pandemic came on the heels of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV), two other highly pathogenic coronavirus spillovers, which collectively have reshaped our view of a virus family previously associated primarily with the common cold. It has placed intense pressure on the collective scientific community to develop therapeutics and vaccines, whose engineering relies on a detailed understanding of coronavirus biology. Here, we present the molecular virology of coronavirus infection, including its entry into cells, its remarkably sophisticated gene expression and replication mechanisms, its extensive remodeling of the intracellular environment and its multi-faceted immune evasion strategies. We highlight aspects of the viral lifecycle that may be amenable to antiviral targeting as well as key features of its biology that await discovery.

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Section: Host Shutoffmentioning

confidence: 99%

The molecular virology of coronaviruses

Hartenian

Nandakumar

Lari

et al. 2020

Journal of Biological Chemistry

423

548

View full text Add to dashboard Cite

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“…on November 1, 2020 by guest http://jvi.asm.org/ Downloaded from PA-X dampens the innate immune response though its host cell shutoff activity, mediated through degradation of cellular mRNAs and disruption of mRNA processing machinery (19,21). The evidence for PA-X playing a role as a virulence factor in avian influenza viruses is unclear, with several studies showing either attenuation or promotion of virulence in vivo (22)(23)(24)(25)(26).…”

Section: Amino Acid Residue 26 In Pa Modulates Plaque Phenotypementioning

confidence: 99%

Contribution of Segment 3 to the Acquisition of Virulence in Contemporary H9N2 Avian Influenza Viruses

Clements

Sealy

Peacock

et al. 2020

J Virol

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H9N2 avian influenza viruses circulate in poultry throughout much of Asia, the Middle East and Africa. These viruses cause huge economic damage to poultry production systems and pose a zoonotic threat both in their own right as well as in the generation of novel zoonotic viruses, for example, H7N9. In recent years it has been observed that H9N2 viruses have further adapted to gallinaceous poultry, becoming more highly transmissible and causing higher morbidity and mortality. Here, we investigate the molecular basis for this increased virulence, comparing a virus from the 1990s and a contemporary field strain. The modern virus replicated to higher titres in various systems and this difference mapped to a single amino acid polymorphism at position 26 of the endonuclease domain shared by the PA and PA-X proteins. This change was responsible for increased replication and higher morbidity and mortality rates along with extended tissue tropism seen in chickens. Although the PA K26E change correlated with increased host cell shutoff activity of the PA-X protein in vitro, it could not be overridden by frameshift site mutations that block PA-X expression and therefore increased PA-X activity could not explain the differences in replication phenotype. Instead, this indicates these differences are due to subtle effects on PA function. This work gives insight into the ongoing evolution and poultry adaptation of H9N2 and other avian influenza viruses and helps us understand the striking morbidity and mortality rates in the field, as well as rapidly expanding geographical range seen in these viruses. Importance Avian influenza viruses, such as H9N2, cause huge economic damage to poultry production worldwide and are additionally considered potential pandemic threats. Understanding how these viruses evolve in their natural hosts is key to effective control strategies. In the Middle East and South Asia an older H9N2 virus strain has been replaced by a new reassortant strain with greater fitness. Here we take representative viruses and investigate the genetic basis for this ‘fitness'. A single mutation in the virus was responsible for greater fitness, enabling high growth of the contemporary H9N2 virus in cells, as well as in chickens. The genetic mutation that modulates this change is within the viral PA protein, a part of the virus polymerase gene that contributes in viral replication as well as contribute in the virus accessory functions – however, we find that the fitness effect is specifically due to changes in the protein polymerase activity.

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“…Indeed, many diverse viruses accelerate basal mRNA decay as an integral part of their lifecycle. These include gammaherpesviruses such as Epstein-Barr virus (EBV) (Rowe et al 2007), Kaposi's sarcoma-associated herpesvirus (KSHV) (Glaunsinger and Ganem 2004;Glaunsinger et al 2005) and murine gammaherpesvirus 68 (MHV68) (Covarrubias et al 2011;Richner et al 2011), alphaherpesvirus such as herpes simplex virus (HSV) (Kwong and Frenkel 1987;Smibert et al 1992;Everly and Read 1997), influenza A (Jagger et al 2012;Desmet et al 2013;Gaucherand et al 2019), vaccinia virus Liu et al 2014), and SARS and MERS coronavirus (Kamitani et al 2006;Kamitani 2009;Lokugamage et al 2015). Most of these viruses encode broad acting, mRNA specific endonucleases (EBV BGLF5, KSHV SOX, MHV68 muSOX, HSV-1 vhs, influenza A PA-X) or decapping factors (vaccinia D9, D10), which create mRNA cleavage products that are directly accessed and cleared by the basal mRNA decay machinery such as Xrn1 (Gaglia et al 2012;.…”

Section: Responding To a Threat: Transcriptional Repression Upon Accementioning

confidence: 99%

“…Most of these viruses encode broad acting, mRNA specific endonucleases (EBV BGLF5, KSHV SOX, MHV68 muSOX, HSV-1 vhs, influenza A PA-X) or decapping factors (vaccinia D9, D10), which create mRNA cleavage products that are directly accessed and cleared by the basal mRNA decay machinery such as Xrn1 (Gaglia et al 2012;. In addition to the infection context, expression of these viral nucleases alone in mammalian cells is sufficient to drive widespread mRNA decay, reducing cytoplasmic mRNA populations by 50-70% (Glaunsinger and Ganem 2004;Gaglia et al 2012;Gaucherand et al 2019;Rodriguez et al 2019).…”

Section: Responding To a Threat: Transcriptional Repression Upon Accementioning

confidence: 99%

Feedback to the central dogma: cytoplasmic mRNA decay and transcription are interdependent processes

Hartenian

Glaunsinger

2019

Critical Reviews in Biochemistry and Molecular Biology

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Transcription and RNA decay are key determinants of gene expression; these processes are typically considered as the uncoupled beginning and end of the messenger RNA (mRNA) lifecycle. Here we describe the growing number of studies demonstrating interplay between these spatially disparate processes in eukaryotes. Specifically, cells can maintain mRNA levels by buffering against changes in mRNA stability or transcription, and can also respond to virally induced accelerated decay by reducing RNA polymerase II gene expression. In addition to these global responses, there is also evidence that mRNAs containing a premature stop codon can cause transcriptional upregulation of homologous genes in a targeted fashion. In each of these systems, RNA binding proteins (RBPs), particularly those involved in mRNA degradation, are critical for cytoplasmic to nuclear communication. Although their specific mechanistic contributions are yet to be fully elucidated, differential trafficking of RBPs between subcellular compartments are likely to play a central role in regulating this gene expression feedback pathway.

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The influenza A virus endoribonuclease PA-X usurps host mRNA processing machinery to limit host gene expression

Cited by 13 publications

References 68 publications

The molecular virology of coronaviruses

The molecular virology of coronaviruses

Contribution of Segment 3 to the Acquisition of Virulence in Contemporary H9N2 Avian Influenza Viruses

Feedback to the central dogma: cytoplasmic mRNA decay and transcription are interdependent processes

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