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Rift Valley fever phlebovirus NSs protein core domain structure suggests molecular basis for nuclear filaments

Rift Valley fever phlebovirus (RVFV) is a clinically and economically important pathogen increasingly likely to cause widespread epidemics. RVFV virulence depends on the interferon antagonist non-structural protein (NSs), which remains poorly characterized. We identified a stable core domain of RVFV...

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Autores principales: Barski, Michal, Brennan, Benjamin, Miller, Ona K, Potter, Jane A, Vijayakrishnan, Swetha, Bhella, David, Naismith, James H, Elliott, Richard M, Schwarz-Linek, Ulrich
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601994/
https://www.ncbi.nlm.nih.gov/pubmed/28915104
http://dx.doi.org/10.7554/eLife.29236
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author Barski, Michal
Brennan, Benjamin
Miller, Ona K
Potter, Jane A
Vijayakrishnan, Swetha
Bhella, David
Naismith, James H
Elliott, Richard M
Schwarz-Linek, Ulrich
author_facet Barski, Michal
Brennan, Benjamin
Miller, Ona K
Potter, Jane A
Vijayakrishnan, Swetha
Bhella, David
Naismith, James H
Elliott, Richard M
Schwarz-Linek, Ulrich
author_sort Barski, Michal
collection PubMed
description Rift Valley fever phlebovirus (RVFV) is a clinically and economically important pathogen increasingly likely to cause widespread epidemics. RVFV virulence depends on the interferon antagonist non-structural protein (NSs), which remains poorly characterized. We identified a stable core domain of RVFV NSs (residues 83–248), and solved its crystal structure, a novel all-helical fold organized into highly ordered fibrils. A hallmark of RVFV pathology is NSs filament formation in infected cell nuclei. Recombinant virus encoding the NSs core domain induced intranuclear filaments, suggesting it contains all essential determinants for nuclear translocation and filament formation. Mutations of key crystal fibril interface residues in viruses encoding full-length NSs completely abrogated intranuclear filament formation in infected cells. We propose the fibrillar arrangement of the NSs core domain in crystals reveals the molecular basis of assembly of this key virulence factor in cell nuclei. Our findings have important implications for fundamental understanding of RVFV virulence.
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spelling pubmed-56019942017-09-19 Rift Valley fever phlebovirus NSs protein core domain structure suggests molecular basis for nuclear filaments Barski, Michal Brennan, Benjamin Miller, Ona K Potter, Jane A Vijayakrishnan, Swetha Bhella, David Naismith, James H Elliott, Richard M Schwarz-Linek, Ulrich eLife Structural Biology and Molecular Biophysics Rift Valley fever phlebovirus (RVFV) is a clinically and economically important pathogen increasingly likely to cause widespread epidemics. RVFV virulence depends on the interferon antagonist non-structural protein (NSs), which remains poorly characterized. We identified a stable core domain of RVFV NSs (residues 83–248), and solved its crystal structure, a novel all-helical fold organized into highly ordered fibrils. A hallmark of RVFV pathology is NSs filament formation in infected cell nuclei. Recombinant virus encoding the NSs core domain induced intranuclear filaments, suggesting it contains all essential determinants for nuclear translocation and filament formation. Mutations of key crystal fibril interface residues in viruses encoding full-length NSs completely abrogated intranuclear filament formation in infected cells. We propose the fibrillar arrangement of the NSs core domain in crystals reveals the molecular basis of assembly of this key virulence factor in cell nuclei. Our findings have important implications for fundamental understanding of RVFV virulence. eLife Sciences Publications, Ltd 2017-09-15 /pmc/articles/PMC5601994/ /pubmed/28915104 http://dx.doi.org/10.7554/eLife.29236 Text en © 2017, Barski et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Structural Biology and Molecular Biophysics
Barski, Michal
Brennan, Benjamin
Miller, Ona K
Potter, Jane A
Vijayakrishnan, Swetha
Bhella, David
Naismith, James H
Elliott, Richard M
Schwarz-Linek, Ulrich
Rift Valley fever phlebovirus NSs protein core domain structure suggests molecular basis for nuclear filaments
title Rift Valley fever phlebovirus NSs protein core domain structure suggests molecular basis for nuclear filaments
title_full Rift Valley fever phlebovirus NSs protein core domain structure suggests molecular basis for nuclear filaments
title_fullStr Rift Valley fever phlebovirus NSs protein core domain structure suggests molecular basis for nuclear filaments
title_full_unstemmed Rift Valley fever phlebovirus NSs protein core domain structure suggests molecular basis for nuclear filaments
title_short Rift Valley fever phlebovirus NSs protein core domain structure suggests molecular basis for nuclear filaments
title_sort rift valley fever phlebovirus nss protein core domain structure suggests molecular basis for nuclear filaments
topic Structural Biology and Molecular Biophysics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601994/
https://www.ncbi.nlm.nih.gov/pubmed/28915104
http://dx.doi.org/10.7554/eLife.29236
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