Influenza virus NS1 protein-RNA interactome reveals intron targeting

Liang Zhang, Juan Wang, Raquel Muñoz-Moreno, Min Kim, Ramanavelan Sakthivel, Wei Mo, Dandan Shao, Aparna Anantharaman, Adolfo García-Sastre, Nicholas K Conrad, Beatriz M Fontoura

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The NS1 protein of influenza A virus is a multifunctional virulence factor that inhibits cellular processes to facilitate viral gene expression. While NS1 is known to interact with RNA and proteins to execute these functions, the cellular RNAs that physically interact with NS1 have not been systematically identified. Here we reveal a NS1 protein-RNA interactome and show that NS1 primarily binds intronic sequences. Among this subset of pre-mRNAs is the RIG-I pre-mRNA, which encodes the main cytoplasmic antiviral sensor of influenza virus infection. This suggested that NS1 interferes with the antiviral response at a posttranscriptional level by virtue of its RNA binding properties. Indeed, we show that NS1 is necessary in the context of viral infection and sufficient upon transfection to decrease the rate of RIG-I intron removal. This NS1 function requires a functional RNA binding domain and is independent of the NS1 interaction with the cleavage and polyadenylation specificity factor CPSF30. NS1 has been previously shown to abrogate RIG-I-mediated antiviral immunity by inhibiting its protein function. Our data further suggest that NS1 also posttranscriptionally alters RIG-I pre-mRNA processing by binding to the RIG-I pre-mRNA. IMPORTANCE A key virulence factor of influenza A virus is the NS1 protein, which inhibits various cellular processes to facilitate viral gene expression. The NS1 protein is localized in the nucleus and in the cytoplasm during infection. In the nucleus, NS1 has functions related to inhibition of gene expression that involve protein-protein and protein-RNA interactions. While several studies have elucidated the protein interactome of NS1, we still lack a clear and systematic understanding of the NS1-RNA interactome. Here we reveal a nuclear NS1-RNA interactome and show that NS1 primarily binds intronic sequences within a subset of pre-mRNAs, including the RIG-I pre-mRNA that encodes the main cytoplasmic antiviral sensor of influenza virus infection. Our data here further suggest that NS1 is necessary and sufficient to impair intron processing of the RIG-I pre-mRNA. These findings support a posttranscriptional role for NS1 in the inhibition of RIG-I expression.

Original languageEnglish (US)
Article numbere0163418
JournalJournal of Virology
Volume92
Issue number24
DOIs
StatePublished - Dec 1 2018

Fingerprint

Orthomyxoviridae
RNA Precursors
Introns
introns
RNA
Antiviral Agents
Proteins
Virus Diseases
proteins
Viral Genes
Virulence Factors
Gene Expression
Cleavage And Polyadenylation Specificity Factor
Influenza A virus
infection
gene expression
Nuclear RNA
virulence
influenza virus INS1 protein
binding properties

Keywords

  • Influenza virus
  • NS1 protein
  • RNA processing

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Zhang, L., Wang, J., Muñoz-Moreno, R., Kim, M., Sakthivel, R., Mo, W., ... Fontoura, B. M. (2018). Influenza virus NS1 protein-RNA interactome reveals intron targeting. Journal of Virology, 92(24), [e0163418]. https://doi.org/10.1128/JVI.01634-18

Influenza virus NS1 protein-RNA interactome reveals intron targeting. / Zhang, Liang; Wang, Juan; Muñoz-Moreno, Raquel; Kim, Min; Sakthivel, Ramanavelan; Mo, Wei; Shao, Dandan; Anantharaman, Aparna; García-Sastre, Adolfo; Conrad, Nicholas K; Fontoura, Beatriz M.

In: Journal of Virology, Vol. 92, No. 24, e0163418, 01.12.2018.

Research output: Contribution to journalArticle

Zhang, L, Wang, J, Muñoz-Moreno, R, Kim, M, Sakthivel, R, Mo, W, Shao, D, Anantharaman, A, García-Sastre, A, Conrad, NK & Fontoura, BM 2018, 'Influenza virus NS1 protein-RNA interactome reveals intron targeting', Journal of Virology, vol. 92, no. 24, e0163418. https://doi.org/10.1128/JVI.01634-18
Zhang L, Wang J, Muñoz-Moreno R, Kim M, Sakthivel R, Mo W et al. Influenza virus NS1 protein-RNA interactome reveals intron targeting. Journal of Virology. 2018 Dec 1;92(24). e0163418. https://doi.org/10.1128/JVI.01634-18
Zhang, Liang ; Wang, Juan ; Muñoz-Moreno, Raquel ; Kim, Min ; Sakthivel, Ramanavelan ; Mo, Wei ; Shao, Dandan ; Anantharaman, Aparna ; García-Sastre, Adolfo ; Conrad, Nicholas K ; Fontoura, Beatriz M. / Influenza virus NS1 protein-RNA interactome reveals intron targeting. In: Journal of Virology. 2018 ; Vol. 92, No. 24.
@article{bd18e7dba05d4c158f6d51abdd267c75,
title = "Influenza virus NS1 protein-RNA interactome reveals intron targeting",
abstract = "The NS1 protein of influenza A virus is a multifunctional virulence factor that inhibits cellular processes to facilitate viral gene expression. While NS1 is known to interact with RNA and proteins to execute these functions, the cellular RNAs that physically interact with NS1 have not been systematically identified. Here we reveal a NS1 protein-RNA interactome and show that NS1 primarily binds intronic sequences. Among this subset of pre-mRNAs is the RIG-I pre-mRNA, which encodes the main cytoplasmic antiviral sensor of influenza virus infection. This suggested that NS1 interferes with the antiviral response at a posttranscriptional level by virtue of its RNA binding properties. Indeed, we show that NS1 is necessary in the context of viral infection and sufficient upon transfection to decrease the rate of RIG-I intron removal. This NS1 function requires a functional RNA binding domain and is independent of the NS1 interaction with the cleavage and polyadenylation specificity factor CPSF30. NS1 has been previously shown to abrogate RIG-I-mediated antiviral immunity by inhibiting its protein function. Our data further suggest that NS1 also posttranscriptionally alters RIG-I pre-mRNA processing by binding to the RIG-I pre-mRNA. IMPORTANCE A key virulence factor of influenza A virus is the NS1 protein, which inhibits various cellular processes to facilitate viral gene expression. The NS1 protein is localized in the nucleus and in the cytoplasm during infection. In the nucleus, NS1 has functions related to inhibition of gene expression that involve protein-protein and protein-RNA interactions. While several studies have elucidated the protein interactome of NS1, we still lack a clear and systematic understanding of the NS1-RNA interactome. Here we reveal a nuclear NS1-RNA interactome and show that NS1 primarily binds intronic sequences within a subset of pre-mRNAs, including the RIG-I pre-mRNA that encodes the main cytoplasmic antiviral sensor of influenza virus infection. Our data here further suggest that NS1 is necessary and sufficient to impair intron processing of the RIG-I pre-mRNA. These findings support a posttranscriptional role for NS1 in the inhibition of RIG-I expression.",
keywords = "Influenza virus, NS1 protein, RNA processing",
author = "Liang Zhang and Juan Wang and Raquel Mu{\~n}oz-Moreno and Min Kim and Ramanavelan Sakthivel and Wei Mo and Dandan Shao and Aparna Anantharaman and Adolfo Garc{\'i}a-Sastre and Conrad, {Nicholas K} and Fontoura, {Beatriz M}",
year = "2018",
month = "12",
day = "1",
doi = "10.1128/JVI.01634-18",
language = "English (US)",
volume = "92",
journal = "Journal of Virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "24",

}

TY - JOUR

T1 - Influenza virus NS1 protein-RNA interactome reveals intron targeting

AU - Zhang, Liang

AU - Wang, Juan

AU - Muñoz-Moreno, Raquel

AU - Kim, Min

AU - Sakthivel, Ramanavelan

AU - Mo, Wei

AU - Shao, Dandan

AU - Anantharaman, Aparna

AU - García-Sastre, Adolfo

AU - Conrad, Nicholas K

AU - Fontoura, Beatriz M

PY - 2018/12/1

Y1 - 2018/12/1

N2 - The NS1 protein of influenza A virus is a multifunctional virulence factor that inhibits cellular processes to facilitate viral gene expression. While NS1 is known to interact with RNA and proteins to execute these functions, the cellular RNAs that physically interact with NS1 have not been systematically identified. Here we reveal a NS1 protein-RNA interactome and show that NS1 primarily binds intronic sequences. Among this subset of pre-mRNAs is the RIG-I pre-mRNA, which encodes the main cytoplasmic antiviral sensor of influenza virus infection. This suggested that NS1 interferes with the antiviral response at a posttranscriptional level by virtue of its RNA binding properties. Indeed, we show that NS1 is necessary in the context of viral infection and sufficient upon transfection to decrease the rate of RIG-I intron removal. This NS1 function requires a functional RNA binding domain and is independent of the NS1 interaction with the cleavage and polyadenylation specificity factor CPSF30. NS1 has been previously shown to abrogate RIG-I-mediated antiviral immunity by inhibiting its protein function. Our data further suggest that NS1 also posttranscriptionally alters RIG-I pre-mRNA processing by binding to the RIG-I pre-mRNA. IMPORTANCE A key virulence factor of influenza A virus is the NS1 protein, which inhibits various cellular processes to facilitate viral gene expression. The NS1 protein is localized in the nucleus and in the cytoplasm during infection. In the nucleus, NS1 has functions related to inhibition of gene expression that involve protein-protein and protein-RNA interactions. While several studies have elucidated the protein interactome of NS1, we still lack a clear and systematic understanding of the NS1-RNA interactome. Here we reveal a nuclear NS1-RNA interactome and show that NS1 primarily binds intronic sequences within a subset of pre-mRNAs, including the RIG-I pre-mRNA that encodes the main cytoplasmic antiviral sensor of influenza virus infection. Our data here further suggest that NS1 is necessary and sufficient to impair intron processing of the RIG-I pre-mRNA. These findings support a posttranscriptional role for NS1 in the inhibition of RIG-I expression.

AB - The NS1 protein of influenza A virus is a multifunctional virulence factor that inhibits cellular processes to facilitate viral gene expression. While NS1 is known to interact with RNA and proteins to execute these functions, the cellular RNAs that physically interact with NS1 have not been systematically identified. Here we reveal a NS1 protein-RNA interactome and show that NS1 primarily binds intronic sequences. Among this subset of pre-mRNAs is the RIG-I pre-mRNA, which encodes the main cytoplasmic antiviral sensor of influenza virus infection. This suggested that NS1 interferes with the antiviral response at a posttranscriptional level by virtue of its RNA binding properties. Indeed, we show that NS1 is necessary in the context of viral infection and sufficient upon transfection to decrease the rate of RIG-I intron removal. This NS1 function requires a functional RNA binding domain and is independent of the NS1 interaction with the cleavage and polyadenylation specificity factor CPSF30. NS1 has been previously shown to abrogate RIG-I-mediated antiviral immunity by inhibiting its protein function. Our data further suggest that NS1 also posttranscriptionally alters RIG-I pre-mRNA processing by binding to the RIG-I pre-mRNA. IMPORTANCE A key virulence factor of influenza A virus is the NS1 protein, which inhibits various cellular processes to facilitate viral gene expression. The NS1 protein is localized in the nucleus and in the cytoplasm during infection. In the nucleus, NS1 has functions related to inhibition of gene expression that involve protein-protein and protein-RNA interactions. While several studies have elucidated the protein interactome of NS1, we still lack a clear and systematic understanding of the NS1-RNA interactome. Here we reveal a nuclear NS1-RNA interactome and show that NS1 primarily binds intronic sequences within a subset of pre-mRNAs, including the RIG-I pre-mRNA that encodes the main cytoplasmic antiviral sensor of influenza virus infection. Our data here further suggest that NS1 is necessary and sufficient to impair intron processing of the RIG-I pre-mRNA. These findings support a posttranscriptional role for NS1 in the inhibition of RIG-I expression.

KW - Influenza virus

KW - NS1 protein

KW - RNA processing

UR - http://www.scopus.com/inward/record.url?scp=85057787449&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85057787449&partnerID=8YFLogxK

U2 - 10.1128/JVI.01634-18

DO - 10.1128/JVI.01634-18

M3 - Article

C2 - 30258002

AN - SCOPUS:85057787449

VL - 92

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 24

M1 - e0163418

ER -