Recognition by host nuclear transport proteins drives disorder-to-order transition in Hendra virus v

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

Abstract

Hendra virus (HeV) is a paramyxovirus that causes lethal disease in humans, for which no vaccine or antiviral agent is available. HeV V protein is central to pathogenesis through its ability to interact with cytoplasmic host proteins, playing key antiviral roles. Here we use immunoprecipitation, siRNA knockdown and confocal laser scanning microscopy to show that HeV V shuttles to and from the nucleus through specific host nuclear transporters. Spectroscopic and small angle X-ray scattering studies reveal HeV V undergoes a disorder-to-order transition upon binding to either importin α/β1 or exportin-1/Ran-GTP, dependent on the V N-terminus. Importantly, we show that specific inhibitors of nuclear transport prevent interaction with host transporters, and reduce HeV infection. These findings emphasize the critical role of host-virus interactions in HeV infection, and potential use of compounds targeting nuclear transport, such as the FDA-approved agent ivermectin, as anti-HeV agents.

Original languageEnglish
Article number358
Number of pages17
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - 10 Jan 2018

Keywords

  • drug development
  • intrinsically disordered proteins
  • protein translocation
  • viral infection

Cite this

@article{0833b64a3cd44534a0f438b1ee0ae4c5,
title = "Recognition by host nuclear transport proteins drives disorder-to-order transition in Hendra virus v",
abstract = "Hendra virus (HeV) is a paramyxovirus that causes lethal disease in humans, for which no vaccine or antiviral agent is available. HeV V protein is central to pathogenesis through its ability to interact with cytoplasmic host proteins, playing key antiviral roles. Here we use immunoprecipitation, siRNA knockdown and confocal laser scanning microscopy to show that HeV V shuttles to and from the nucleus through specific host nuclear transporters. Spectroscopic and small angle X-ray scattering studies reveal HeV V undergoes a disorder-to-order transition upon binding to either importin α/β1 or exportin-1/Ran-GTP, dependent on the V N-terminus. Importantly, we show that specific inhibitors of nuclear transport prevent interaction with host transporters, and reduce HeV infection. These findings emphasize the critical role of host-virus interactions in HeV infection, and potential use of compounds targeting nuclear transport, such as the FDA-approved agent ivermectin, as anti-HeV agents.",
keywords = "drug development, intrinsically disordered proteins, protein translocation, viral infection",
author = "Atkinson, {Sarah C.} and Audsley, {Michelle D.} and Lieu, {Kim G.} and Marsh, {Glenn A.} and Thomas, {David R.} and Heaton, {Steven M.} and Paxman, {Jason J.} and Wagstaff, {Kylie M.} and Buckle, {Ashley M.} and Moseley, {Gregory W.} and Jans, {David A.} and Borg, {Natalie A.}",
year = "2018",
month = "1",
day = "10",
doi = "10.1038/s41598-017-18742-8",
language = "English",
volume = "8",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

Recognition by host nuclear transport proteins drives disorder-to-order transition in Hendra virus v. / Atkinson, Sarah C.; Audsley, Michelle D.; Lieu, Kim G.; Marsh, Glenn A.; Thomas, David R.; Heaton, Steven M.; Paxman, Jason J.; Wagstaff, Kylie M.; Buckle, Ashley M.; Moseley, Gregory W.; Jans, David A.; Borg, Natalie A.

In: Scientific Reports, Vol. 8, No. 1, 358, 10.01.2018.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Recognition by host nuclear transport proteins drives disorder-to-order transition in Hendra virus v

AU - Atkinson, Sarah C.

AU - Audsley, Michelle D.

AU - Lieu, Kim G.

AU - Marsh, Glenn A.

AU - Thomas, David R.

AU - Heaton, Steven M.

AU - Paxman, Jason J.

AU - Wagstaff, Kylie M.

AU - Buckle, Ashley M.

AU - Moseley, Gregory W.

AU - Jans, David A.

AU - Borg, Natalie A.

PY - 2018/1/10

Y1 - 2018/1/10

N2 - Hendra virus (HeV) is a paramyxovirus that causes lethal disease in humans, for which no vaccine or antiviral agent is available. HeV V protein is central to pathogenesis through its ability to interact with cytoplasmic host proteins, playing key antiviral roles. Here we use immunoprecipitation, siRNA knockdown and confocal laser scanning microscopy to show that HeV V shuttles to and from the nucleus through specific host nuclear transporters. Spectroscopic and small angle X-ray scattering studies reveal HeV V undergoes a disorder-to-order transition upon binding to either importin α/β1 or exportin-1/Ran-GTP, dependent on the V N-terminus. Importantly, we show that specific inhibitors of nuclear transport prevent interaction with host transporters, and reduce HeV infection. These findings emphasize the critical role of host-virus interactions in HeV infection, and potential use of compounds targeting nuclear transport, such as the FDA-approved agent ivermectin, as anti-HeV agents.

AB - Hendra virus (HeV) is a paramyxovirus that causes lethal disease in humans, for which no vaccine or antiviral agent is available. HeV V protein is central to pathogenesis through its ability to interact with cytoplasmic host proteins, playing key antiviral roles. Here we use immunoprecipitation, siRNA knockdown and confocal laser scanning microscopy to show that HeV V shuttles to and from the nucleus through specific host nuclear transporters. Spectroscopic and small angle X-ray scattering studies reveal HeV V undergoes a disorder-to-order transition upon binding to either importin α/β1 or exportin-1/Ran-GTP, dependent on the V N-terminus. Importantly, we show that specific inhibitors of nuclear transport prevent interaction with host transporters, and reduce HeV infection. These findings emphasize the critical role of host-virus interactions in HeV infection, and potential use of compounds targeting nuclear transport, such as the FDA-approved agent ivermectin, as anti-HeV agents.

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