Dual modes of rabies P-protein association with microtubules: a novel strategy to suppress the antiviral response

Gregory William Moseley, Xavier Lahaye, Daniela Martino Roth, Sibil Oksayan, Richard P Filmer, Caitlin Lorraine Rowe, Danielle Blondel, David Andrew Jans

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Conventional nuclear import is independent of the cytoskeleton, but recent data have shown that the import of specific proteins can be either facilitated or inhibited by microtubules (MTs). Nuclear import of the P-protein from rabies virus involves a MT-facilitated mechanism, but here, we show that P-protein is unique in that it also undergoes MT-inhibited import, with the mode of MT-interaction being regulated by the oligomeric state of the P-protein. This is the first demonstration that a protein can utilise both MT-inhibited and MT-facilitated import mechanisms, and can switch between these different modes of MT interaction to regulate its nuclear trafficking. Importantly, we show that the P-protein exploits MT-dependent mechanisms to manipulate host cell processes by switching the import of the interferon-activated transcription factor STAT1 from a conventional to a MT-inhibited mechanism. This prevents STAT1 nuclear import and signalling in response to interferon, which is vital to the host innate antiviral response. This is the first report of MT involvement in the viral subversion of interferon signalling that is central to virus pathogenicity, and identifies novel targets for the development of antiviral drugs or attenuated viruses for vaccine applications.
Original languageEnglish
Pages (from-to)3652 - 3662
Number of pages11
JournalJournal of Cell Science
Volume122
Issue number20
DOIs
Publication statusPublished - 2009

Cite this

Moseley, Gregory William ; Lahaye, Xavier ; Martino Roth, Daniela ; Oksayan, Sibil ; Filmer, Richard P ; Rowe, Caitlin Lorraine ; Blondel, Danielle ; Jans, David Andrew. / Dual modes of rabies P-protein association with microtubules: a novel strategy to suppress the antiviral response. In: Journal of Cell Science. 2009 ; Vol. 122, No. 20. pp. 3652 - 3662.
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abstract = "Conventional nuclear import is independent of the cytoskeleton, but recent data have shown that the import of specific proteins can be either facilitated or inhibited by microtubules (MTs). Nuclear import of the P-protein from rabies virus involves a MT-facilitated mechanism, but here, we show that P-protein is unique in that it also undergoes MT-inhibited import, with the mode of MT-interaction being regulated by the oligomeric state of the P-protein. This is the first demonstration that a protein can utilise both MT-inhibited and MT-facilitated import mechanisms, and can switch between these different modes of MT interaction to regulate its nuclear trafficking. Importantly, we show that the P-protein exploits MT-dependent mechanisms to manipulate host cell processes by switching the import of the interferon-activated transcription factor STAT1 from a conventional to a MT-inhibited mechanism. This prevents STAT1 nuclear import and signalling in response to interferon, which is vital to the host innate antiviral response. This is the first report of MT involvement in the viral subversion of interferon signalling that is central to virus pathogenicity, and identifies novel targets for the development of antiviral drugs or attenuated viruses for vaccine applications.",
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Dual modes of rabies P-protein association with microtubules: a novel strategy to suppress the antiviral response. / Moseley, Gregory William; Lahaye, Xavier; Martino Roth, Daniela; Oksayan, Sibil; Filmer, Richard P; Rowe, Caitlin Lorraine; Blondel, Danielle; Jans, David Andrew.

In: Journal of Cell Science, Vol. 122, No. 20, 2009, p. 3652 - 3662.

Research output: Contribution to journalArticleResearchpeer-review

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