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

2018 ◽  
Author(s):  
Lea Gaucherand ◽  
Brittany K. Porter ◽  
Summer K. Schmaling ◽  
Christopher Harley Rycroft ◽  
Yuzo Kevorkian ◽  
...  
Keyword(s):  
Gene Expression ◽  
Influenza A Virus ◽  
Rna Splicing ◽  
Influenza A ◽  
Host Gene ◽  
Host Gene Expression ◽  
Viral Control ◽  
New Host ◽  
Antiviral Responses ◽  
Host Shutoff

SUMMARYMany viruses globally shut off host gene expression to inhibit activation of cell-intrinsic antiviral responses. However, host shutoff is not indiscriminate, since viral proteins and host proteins required for viral replication are still synthesized during shutoff. The molecular determinants of target selectivity in host shutoff remain incompletely understood. Here, we report that the influenza A virus shutoff factor PA-X usurps RNA splicing to selectively target host RNAs for destruction. PA-X preferentially degrades spliced mRNAs, both transcriptome-wide and in reporter assays. Moreover, proximity-labeling proteomics revealed that PA-X interacts with cellular proteins involved in RNA splicing. The interaction with splicing contributes to target discrimination and is unique among viral host shutoff nucleases. This novel mechanism sheds light on the specificity of viral control of host gene expression and may provide opportunities for development of new host-targeted antivirals.

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

Cell Reports ◽  
2019 ◽  
Vol 27 (3) ◽  
pp. 776-792.e7 ◽  
Author(s):  
Lea Gaucherand ◽  
Brittany K. Porter ◽  
Rachel E. Levene ◽  
Emma L. Price ◽  
Summer K. Schmaling ◽  
...  
Keyword(s):  
Gene Expression ◽  
Influenza A Virus ◽  
Influenza A ◽  
Mrna Processing ◽  
Host Gene ◽  
Host Gene Expression ◽  
Processing Machinery

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

Viruses ◽  
2016 ◽  
Vol 8 (4) ◽  
pp. 102 ◽  
Author(s):  
Hembly Rivas ◽  
Summer Schmaling ◽  
Marta Gaglia
Keyword(s):  
Gene Expression ◽  
Influenza A Virus ◽  
Influenza A ◽  
Host Gene ◽  
Host Gene Expression

scholarly journals Amino Acid Residues Involved in Inhibition of Host Gene Expression by Influenza A/Brevig Mission/1/1918 PA-X

2021 ◽  
Vol 9 (5) ◽  
pp. 1109
Author(s):  
Kevin Chiem ◽  
Luis Martinez-Sobrido ◽  
Aitor Nogales ◽  
Marta L. DeDiego
Keyword(s):  
Gene Expression ◽  
Amino Acid ◽  
Influenza A ◽  
Host Gene ◽  
Amino Acid Residues ◽  
Host Gene Expression ◽  
T7 Promoter ◽  
Antiviral Responses ◽  
Novel Approach ◽  
Identify Amino Acid

The influenza A virus (IAV) PA-X protein is a virulence factor that selectively degrades host mRNAs leading to protein shutoff. This function modulates host inflammation, antiviral responses, cell apoptosis, and pathogenesis. In this work we describe a novel approach based on the use of bacteria and plasmid encoding of the PA-X gene under the control of the bacteriophage T7 promoter to identify amino acid residues important for A/Brevig Mission/1/1918 H1N1 PA-X’s shutoff activity. Using this system, we have identified PA-X mutants encoding single or double amino acid changes, which diminish its host shutoff activity, as well as its ability to counteract interferon responses upon viral infection. This novel bacteria-based approach could be used for the identification of viral proteins that inhibit host gene expression as well as the amino acid residues responsible for inhibition of host gene expression.

scholarly journals Inter-Species Host Gene Expression Differences in Response to Human and Avian Influenza A Virus Strains

2017 ◽  
Vol 18 (11) ◽  
pp. 2295 ◽  
Author(s):  
Biruhalem Taye ◽  
Dawn Yeo ◽  
Raphael Lee ◽  
Boon Tan ◽  
Richard Sugrue ◽  
...  
Keyword(s):  
Gene Expression ◽  
Avian Influenza ◽  
Influenza A Virus ◽  
Influenza A ◽  
Host Gene ◽  
Host Gene Expression ◽  
Avian Influenza A Virus ◽  
Virus Strains

scholarly journals Amino acid residues involved in inhibition of host gene expression by influenza A/Brevig Mission/1/1918 PA-X

2021 ◽  
Author(s):  
Kevin Chiem ◽  
Luis Martinez-Sobrido ◽  
Aitor Nogales ◽  
Marta L. DeDiego
Keyword(s):  
Gene Expression ◽  
Amino Acid ◽  
Influenza A ◽  
Host Gene ◽  
Amino Acid Residues ◽  
Host Gene Expression ◽  
T7 Promoter ◽  
Antiviral Responses ◽  
Novel Approach ◽  
Identify Amino Acid

AbstractInfluenza A virus (IAV) PA-X protein is a virulence factor that selectively degrades host mRNAs leading to protein shutoff. This function modulates host inflammation, antiviral responses, cell apoptosis, and pathogenesis. In this work we describe a novel approach based on the use of bacteria and a plasmid encoding the PA-X gene under the control of the bacteriophage T7 promoter to identify amino acid residues important for A/Brevig Mission/1/1918 H1N1 PA-X’s shutoff activity. Using this system, we have identified PA-X mutants encoding single or double amino acid changes, which diminish its host shutoff activity, as well as its ability to counteract interferon responses upon viral infection. This novel bacteria-based approach could be used for the identification of viral proteins that inhibit host gene expression as well as the amino acid residues responsible for inhibition of host gene expression.

scholarly journals Host Shutoff in Influenza A Virus: Many Means to an End

Viruses ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 475 ◽  
Author(s):  
Rachel Levene ◽  
Marta Gaglia
Keyword(s):  
Immune Responses ◽  
Influenza A Virus ◽  
Influenza A ◽  
Rna Synthesis ◽  
Viral Proteins ◽  
Host Gene Expression ◽  
Structural Protein ◽  
Infected Cells ◽  
Host Shutoff ◽  
Virus Replication Cycle

Influenza A virus carries few of its own proteins, but uses them effectively to take control of the infected cells and avoid immune responses. Over the years, host shutoff, the widespread down-regulation of host gene expression, has emerged as a key process that contributes to cellular takeover in infected cells. Interestingly, multiple mechanisms of host shutoff have been described in influenza A virus, involving changes in translation, RNA synthesis and stability. Several viral proteins, notably the non-structural protein NS1, the RNA-dependent RNA polymerase and the endoribonuclease PA-X have been implicated in host shutoff. This multitude of host shutoff mechanisms indicates that host shutoff is an important component of the influenza A virus replication cycle. Here we review the various mechanisms of host shutoff in influenza A virus and the evidence that they contribute to immune evasion and/or viral replication. We also discuss what the purpose of having multiple mechanisms may be.

scholarly journals Functional Evolution of Influenza Virus NS1 Protein in Currently Circulating Human 2009 Pandemic H1N1 Viruses

2017 ◽  
Vol 91 (17) ◽  
Author(s):  
Amelia M. Clark ◽  
Aitor Nogales ◽  
Luis Martinez-Sobrido ◽  
David J. Topham ◽  
Marta L. DeDiego
Keyword(s):  
Gene Expression ◽  
Influenza Virus ◽  
Amino Acid ◽  
Proinflammatory Cytokines ◽  
Influenza A ◽  
Host Gene ◽  
Pandemic H1n1 ◽  
Ns1 Protein ◽  
Host Gene Expression ◽  
Mouse Lungs

ABSTRACT In 2009, a novel H1N1 influenza virus emerged in humans, causing a global pandemic. It was previously shown that the NS1 protein from this human 2009 pandemic H1N1 (pH1N1) virus was an effective interferon (IFN) antagonist but could not inhibit general host gene expression, unlike other NS1 proteins from seasonal human H1N1 and H3N2 viruses. Here we show that the NS1 protein from currently circulating pH1N1 viruses has evolved to encode 6 amino acid changes (E55K, L90I, I123V, E125D, K131E, and N205S) with respect to the original protein. Notably, these 6 residue changes restore the ability of pH1N1 NS1 to inhibit general host gene expression, mainly by their ability to restore binding to the cellular factor CPSF30. This is the first report describing the ability of the pH1N1 NS1 protein to naturally acquire mutations that restore this function. Importantly, a recombinant pH1N1 virus containing these 6 amino acid changes in the NS1 protein (pH1N1/NSs-6mut) inhibited host IFN and proinflammatory responses to a greater extent than that with the parental virus (pH1N1/NS1-wt), yet virus titers were not significantly increased in cell cultures or in mouse lungs, and the disease was partially attenuated. The pH1N1/NSs-6mut virus grew similarly to pH1N1/NSs-wt in mouse lungs, but infection with pH1N1/NSs-6mut induced lower levels of proinflammatory cytokines, likely due to a general inhibition of gene expression mediated by the mutated NS1 protein. This lower level of inflammation induced by the pH1N1/NSs-6mut virus likely accounts for the attenuated disease phenotype and may represent a host-virus adaptation affecting influenza virus pathogenesis. IMPORTANCE Seasonal influenza A viruses (IAVs) are among the most common causes of respiratory infections in humans. In addition, occasional pandemics are caused when IAVs circulating in other species emerge in the human population. In 2009, a swine-origin H1N1 IAV (pH1N1) was transmitted to humans, infecting people then and up to the present. It was previously shown that the NS1 protein from the 2009 pandemic H1N1 (pH1N1) virus is not able to inhibit general gene expression. However, currently circulating pH1N1 viruses have evolved to encode 6 amino acid changes (E55K, L90I, I123V, E125D, K131E, and N205S) that allow the NS1 protein of contemporary pH1N1 strains to inhibit host gene expression, which correlates with its ability to interact with CPSF30. Infection with a recombinant pH1N1 virus encoding these 6 amino acid changes (pH1N1/NSs-6mut) induced lower levels of proinflammatory cytokines, resulting in viral attenuation in vivo. This might represent an adaptation of pH1N1 virus to humans.

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