Ebola Virus VP24 Targets a Unique NLS Binding Site on Karyopherin Alpha 5 to Selectively Compete with Nuclear Import of Phosphorylated STAT1

• Published in: Cell host & microbe Vol. 16; no. 2; pp. 187 - 200
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13-08-2014
• Subjects: Active Transport, Cell Nucleus; alpha Karyopherins - chemistry; Binding, Competitive; Cell Nucleus - metabolism; Crystallography, X-Ray; Ebolavirus - physiology; HEK293 Cells; Humans; Hydrogen Bonding; Models, Molecular; Nuclear Localization Signals; Phosphoproteins - metabolism; Protein Interaction Domains and Motifs; STAT1 Transcription Factor - metabolism; Viral Proteins - chemistry; Viral Proteins - metabolism
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2014.07.008

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.
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•Structure of Ebola virus VP24 bound to the C terminus of karyopherin alpha 5 (KPNA5)•VP24 binds a unique nonclassical NLS binding site in KPNA5•VP24 and phosphorylated STAT1 share a common binding site on KPNA5 binding•VP24 competes with nuclear import of phosphorylated STAT1 to counter STAT signaling
Ebola virus VP24 (eVP24) inhibits host interferon responses during infection. Xu et al. determined the structure of eVP24 in complex with the nuclear import protein karyopherin alpha 5. eVP24 selectively binds to and competes with phosphorylated STAT1 for a unique nuclear localization signal binding site on karyopherin alpha to counter interferon signaling.