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
Author Information
Wei Xu: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
Megan R Edwards: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Dominika M Borek: Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Alicia R Feagins: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Anuradha Mittal: Department of Biomedical Engineering and Center for Biological Systems Engineering, Washington University, St. Louis, MO 63110, USA.
Joshua B Alinger: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
Kayla N Berry: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
Benjamin Yen: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Jennifer Hamilton: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Tom J Brett: Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Rohit V Pappu: Department of Biomedical Engineering and Center for Biological Systems Engineering, Washington University, St. Louis, MO 63110, USA.
Daisy W Leung: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
Christopher F Basler: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Gaya K Amarasinghe: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA. Electronic address: gamarasinghe@path.wustl.edu.
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.
Associated Data
PDB | 4U2X
References
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):235-42
[PMID: 21460441]
