Ebola virus VP24 targets a unique NLS binding site on karyopherin alpha 5 to selectively compete with nuclear import of phosphorylated STAT1

Wei Xu, Megan R. Edwards, Dominika M. Borek, Alicia R. Feagins, Anuradha Mittal, Joshua B. Alinger, Kayla N. Berry, Benjamin Yen, Jennifer Hamilton, Tom J. Brett, Rohit V. Pappu, Daisy W. Leung, Christopher F. Basler, Gaya K. Amarasinghe

Research output: Contribution to journalArticle

128 Citations (Scopus)

Abstract

Summary During antiviral defense, interferon (IFN) signaling triggers nuclear transport of tyrosine-phosphorylated STAT1 (PY-STAT1), which occurs via a subset of karyopherin alpha (KPNA) nuclear transporters. Many viruses, including Ebola virus, actively antagonize STAT1 signaling to counteract the antiviral effects of IFN. Ebola virus VP24 protein (eVP24) binds KPNA to inhibit PY-STAT1 nuclear transport and render cells refractory to IFNs. We describe the structure of human KPNA5 C terminus in complex with eVP24. In the complex, eVP24 recognizes a unique nonclassical nuclear localization signal (NLS) binding site on KPNA5 that is necessary for efficient PY-STAT1 nuclear transport. eVP24 binds KPNA5 with very high affinity to effectively compete with and inhibit PY-STAT1 nuclear transport. In contrast, eVP24 binding does not affect the transport of classical NLS cargo. Thus, eVP24 counters cell-intrinsic innate immunity by selectively targeting PY-STAT1 nuclear import while leaving the transport of other cargo that may be required for viral replication unaffected.

Original languageEnglish (US)
Pages (from-to)187-200
Number of pages14
JournalCell Host and Microbe
Volume16
Issue number2
DOIs
StatePublished - Aug 13 2014

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alpha Karyopherins
Ebolavirus
Nuclear Localization Signals
Cell Nucleus Active Transport
Binding Sites
Interferons
Antiviral Agents
Innate Immunity
Tyrosine
Viruses

ASJC Scopus subject areas

  • Immunology and Microbiology(all)
  • Cancer Research
  • Molecular Biology

Cite this

Ebola virus VP24 targets a unique NLS binding site on karyopherin alpha 5 to selectively compete with nuclear import of phosphorylated STAT1. / Xu, Wei; Edwards, Megan R.; Borek, Dominika M.; Feagins, Alicia R.; Mittal, Anuradha; Alinger, Joshua B.; Berry, Kayla N.; Yen, Benjamin; Hamilton, Jennifer; Brett, Tom J.; Pappu, Rohit V.; Leung, Daisy W.; Basler, Christopher F.; Amarasinghe, Gaya K.

In: Cell Host and Microbe, Vol. 16, No. 2, 13.08.2014, p. 187-200.

Research output: Contribution to journalArticle

Xu, W, Edwards, MR, Borek, DM, Feagins, AR, Mittal, A, Alinger, JB, Berry, KN, Yen, B, Hamilton, J, Brett, TJ, Pappu, RV, Leung, DW, Basler, CF & Amarasinghe, GK 2014, 'Ebola virus VP24 targets a unique NLS binding site on karyopherin alpha 5 to selectively compete with nuclear import of phosphorylated STAT1', Cell Host and Microbe, vol. 16, no. 2, pp. 187-200. https://doi.org/10.1016/j.chom.2014.07.008
Xu, Wei ; Edwards, Megan R. ; Borek, Dominika M. ; Feagins, Alicia R. ; Mittal, Anuradha ; Alinger, Joshua B. ; Berry, Kayla N. ; Yen, Benjamin ; Hamilton, Jennifer ; Brett, Tom J. ; Pappu, Rohit V. ; Leung, Daisy W. ; Basler, Christopher F. ; Amarasinghe, Gaya K. / Ebola virus VP24 targets a unique NLS binding site on karyopherin alpha 5 to selectively compete with nuclear import of phosphorylated STAT1. In: Cell Host and Microbe. 2014 ; Vol. 16, No. 2. pp. 187-200.
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