Effects of mutations in the effector domain of influenza A virus NS1 protein

Carina Pereira; Helen Wise; Dominic Thekkedath Kurian; Rute Pinto; Maria Joao Amorim; Andrew Gill; Paul Digard

doi:10.1186/s13104-018-3779-6

Effects of mutations in the effector domain of influenza A virus NS1 protein

Carina Pereira, Helen Wise, Dominic Thekkedath Kurian, Rute Pinto, Maria Joao Amorim, Andrew Gill, Paul Digard

Royal (Dick) School of Veterinary Studies

Research output: Contribution to journal › Article › peer-review

Abstract

Objective: The multifunctional NS1 protein of influenza A virus has roles in antagonising cellular innate immune responses and promoting viral gene expression. To better understand the interplay between these functions, we
tested the effects of NS1 effector domain mutations known to affect homo-dimerisation or interactions with cellular PI3 kinase or Trim25 on NS1 ability to promote nuclear export of viral mRNAs. Results: The NS1 dimerisation mutant W187R retained the functions of binding cellular NXF1 as well as stabilising
NXF1 interaction with viral segment 7 mRNAs and promoting their nuclear export. Two PI3K-binding mutants, NS1 Y89F and Y89A still bound NXF1 but no longer promoted NXF1 interactions with segment 7 mRNA or its nuclear
export. The Trim25-binding mutant NS1 E96A/E97A bound NXF1 and supported NXF1 interactions with segment 7 mRNA but no longer supported mRNA nuclear export. Analysis of WT and mutant NS1 interaction partners identified
hsp70 as specifically binding to NS1 E96A/E97A. Whilst these data suggest the possibility of functional links between NS1’s effects on intracellular signalling and its role in viral mRNA nuclear export, they also indicate potential
pleiotropic effects of the NS1 mutations; in the case of E96A/E97A possibly via disrupted protein folding leading to chaperone recruitment.

Original language	English
Article number	673
Journal	BMC Research Notes
Volume	11
Issue number	1
Early online date	18 Sept 2018
DOIs	https://doi.org/10.1186/s13104-018-3779-6
Publication status	E-pub ahead of print - 18 Sept 2018

Keywords / Materials (for Non-textual outputs)

Influenza A virus
NS1
PI3K
Trim25
RIG-I
Nuclear export

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10.1186/s13104-018-3779-6

Effects of mutations in the effector domain of influenza A virus NS1 protein
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ISP 2 2017/22 Control of Infectious Diseases
Gally, D. (Principal Investigator)
Biotechnology and Biological Sciences Research Council
1/04/17 → 31/03/22
Project: Research

Proteomics and Metabolomics Facility - Roslin Institute
Kurian, D. (Manager)
Royal (Dick) School of Veterinary Studies
Facility/equipment: Facility

Cite this

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title = "Effects of mutations in the effector domain of influenza A virus NS1 protein",

abstract = "Objective: The multifunctional NS1 protein of influenza A virus has roles in antagonising cellular innate immune responses and promoting viral gene expression. To better understand the interplay between these functions, we tested the effects of NS1 effector domain mutations known to affect homo-dimerisation or interactions with cellular PI3 kinase or Trim25 on NS1 ability to promote nuclear export of viral mRNAs. Results: The NS1 dimerisation mutant W187R retained the functions of binding cellular NXF1 as well as stabilising NXF1 interaction with viral segment 7 mRNAs and promoting their nuclear export. Two PI3K-binding mutants, NS1 Y89F and Y89A still bound NXF1 but no longer promoted NXF1 interactions with segment 7 mRNA or its nuclear export. The Trim25-binding mutant NS1 E96A/E97A bound NXF1 and supported NXF1 interactions with segment 7 mRNA but no longer supported mRNA nuclear export. Analysis of WT and mutant NS1 interaction partners identified hsp70 as specifically binding to NS1 E96A/E97A. Whilst these data suggest the possibility of functional links between NS1{\textquoteright}s effects on intracellular signalling and its role in viral mRNA nuclear export, they also indicate potential pleiotropic effects of the NS1 mutations; in the case of E96A/E97A possibly via disrupted protein folding leading to chaperone recruitment.",

keywords = "Influenza A virus, NS1, PI3K, Trim25, RIG-I, Nuclear export",

author = "Carina Pereira and Helen Wise and \{Thekkedath Kurian\}, Dominic and Rute Pinto and Amorim, \{Maria Joao\} and Andrew Gill and Paul Digard",

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doi = "10.1186/s13104-018-3779-6",

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AU - Pereira, Carina

AU - Wise, Helen

AU - Thekkedath Kurian, Dominic

AU - Pinto, Rute

AU - Amorim, Maria Joao

AU - Gill, Andrew

AU - Digard, Paul

PY - 2018/9/18

Y1 - 2018/9/18

N2 - Objective: The multifunctional NS1 protein of influenza A virus has roles in antagonising cellular innate immune responses and promoting viral gene expression. To better understand the interplay between these functions, we tested the effects of NS1 effector domain mutations known to affect homo-dimerisation or interactions with cellular PI3 kinase or Trim25 on NS1 ability to promote nuclear export of viral mRNAs. Results: The NS1 dimerisation mutant W187R retained the functions of binding cellular NXF1 as well as stabilising NXF1 interaction with viral segment 7 mRNAs and promoting their nuclear export. Two PI3K-binding mutants, NS1 Y89F and Y89A still bound NXF1 but no longer promoted NXF1 interactions with segment 7 mRNA or its nuclear export. The Trim25-binding mutant NS1 E96A/E97A bound NXF1 and supported NXF1 interactions with segment 7 mRNA but no longer supported mRNA nuclear export. Analysis of WT and mutant NS1 interaction partners identified hsp70 as specifically binding to NS1 E96A/E97A. Whilst these data suggest the possibility of functional links between NS1’s effects on intracellular signalling and its role in viral mRNA nuclear export, they also indicate potential pleiotropic effects of the NS1 mutations; in the case of E96A/E97A possibly via disrupted protein folding leading to chaperone recruitment.

AB - Objective: The multifunctional NS1 protein of influenza A virus has roles in antagonising cellular innate immune responses and promoting viral gene expression. To better understand the interplay between these functions, we tested the effects of NS1 effector domain mutations known to affect homo-dimerisation or interactions with cellular PI3 kinase or Trim25 on NS1 ability to promote nuclear export of viral mRNAs. Results: The NS1 dimerisation mutant W187R retained the functions of binding cellular NXF1 as well as stabilising NXF1 interaction with viral segment 7 mRNAs and promoting their nuclear export. Two PI3K-binding mutants, NS1 Y89F and Y89A still bound NXF1 but no longer promoted NXF1 interactions with segment 7 mRNA or its nuclear export. The Trim25-binding mutant NS1 E96A/E97A bound NXF1 and supported NXF1 interactions with segment 7 mRNA but no longer supported mRNA nuclear export. Analysis of WT and mutant NS1 interaction partners identified hsp70 as specifically binding to NS1 E96A/E97A. Whilst these data suggest the possibility of functional links between NS1’s effects on intracellular signalling and its role in viral mRNA nuclear export, they also indicate potential pleiotropic effects of the NS1 mutations; in the case of E96A/E97A possibly via disrupted protein folding leading to chaperone recruitment.

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Effects of mutations in the effector domain of influenza A virus NS1 protein

Abstract

Keywords / Materials (for Non-textual outputs)

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Projects

ISP 2 2017/22 Control of Infectious Diseases

Equipment

Proteomics and Metabolomics Facility - Roslin Institute

Cite this