@article{1ae0a9765e834644865acb47d61fcb55,
title = "Ebola virus VP24 targets a unique NLS binding site on karyopherin alpha 5 to selectively compete with nuclear import of phosphorylated STAT1",
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.",
author = "Wei Xu and Edwards, {Megan R.} and Borek, {Dominika M.} and Feagins, {Alicia R.} and Anuradha Mittal and Alinger, {Joshua B.} and Berry, {Kayla N.} and Benjamin Yen and Jennifer Hamilton and Brett, {Tom J.} and Pappu, {Rohit V.} and Leung, {Daisy W.} and Basler, {Christopher F.} and Amarasinghe, {Gaya K.}",
note = "Funding Information: We thank Drs. M. Diamond, K. Murphy, and H. Virgin for critical reading of the manuscript and discussions; Drs. T. Ellenberger, D. Fremont, N. Tolia, and M. Holtzman for discussion; Drs. W. Li and Z. Otwinowski for discussions and help with initial model building of low-resolution data; Dr. Y. Chook for discussions and reagents; Drs. I. Macara and R. Bose for reagents; members of the Amarasinghe and Basler laboratories for experimental support; the Microscopy Shared Resource Facility at the Icahn School of Medicine at Mount Sinai; and Drs. S. Ginell, N. Duke, and J. Lazarz at Advanced Photon Source (APS) Sector 19 and Dr. Jay Nix at Advanced Light Source (ALS) 4.2.2 for beamline access and assistance. Use of Structural Biology Center beamlines at the APS is supported by the US D.O.E. under contract DE-AC02-06CH11357 . The ALS is supported by the Director, Office of Science, Office of Basic Energy Sciences, of the US Department of Energy under Contract No. DE-AC02-05CH11231 . This study also made use of the National Magnetic Resonance Facility at Madison, which is supported by NIH grant P41GM103399 (NIGMS). This work is supported in part by the US NSF ( MCB-1121867 to R.V.P.) and NIH grants (J.A.B. and K.N.B. supported by T32GM07200 ; R01HL119813 to T.J.B; R01AI107056 to D.W.L.; R01AI059536 to C.F.B.; U19AI109945 [Basler-PI] and U19AI109664 [Basler-PI] to C.F.B. and G.K.A.; U19AI070489 [Holtzman-PI] and R01AI081914 to G.K.A). ",
year = "2014",
month = aug,
day = "13",
doi = "10.1016/j.chom.2014.07.008",
language = "English (US)",
volume = "16",
pages = "187--200",
journal = "Cell Host and Microbe",
issn = "1931-3128",
publisher = "Cell Press",
number = "2",
}