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Virus-Cell Interactions

Differential Disruption of Nucleocytoplasmic Trafficking Pathways by Rhinovirus 2A Proteases

Kelly Watters, Bahar Inankur, Jaye C. Gardiner, Jay Warrick, Nathan M. Sherer, John Yin, Ann C. Palmenberg
Terence S. Dermody, Editor
Kelly Watters
aInstitute for Molecular Virology, University of Wisconsin—Madison, Madison, Wisconsin, USA
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Bahar Inankur
bWisconsin Institutes for Discovery and Department of Chemical and Biological Engineering, University of Wisconsin—Madison, Madison, Wisconsin, USA
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Jaye C. Gardiner
aInstitute for Molecular Virology, University of Wisconsin—Madison, Madison, Wisconsin, USA
dMcArdle Laboratories for Cancer Research, University of Wisconsin—Madison, Madison, Wisconsin, USA
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Jay Warrick
cWisconsin Institutes for Medical Research and Department of Biomedical Engineering, University of Wisconsin—Madison, Madison, Wisconsin, USA
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Nathan M. Sherer
aInstitute for Molecular Virology, University of Wisconsin—Madison, Madison, Wisconsin, USA
dMcArdle Laboratories for Cancer Research, University of Wisconsin—Madison, Madison, Wisconsin, USA
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John Yin
bWisconsin Institutes for Discovery and Department of Chemical and Biological Engineering, University of Wisconsin—Madison, Madison, Wisconsin, USA
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Ann C. Palmenberg
aInstitute for Molecular Virology, University of Wisconsin—Madison, Madison, Wisconsin, USA
eDepartment of Biochemistry, University of Wisconsin—Madison, Madison, Wisconsin, USA
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Terence S. Dermody
University of Pittsburgh School of Medicine
Roles: Editor
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DOI: 10.1128/JVI.02472-16
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ABSTRACT

The RNA rhinoviruses (RV) encode 2A proteases (2Apro) that contribute essential polyprotein processing and host cell shutoff functions during infection, including the cleavage of Phe/Gly-containing nucleoporin proteins (Nups) within nuclear pore complexes (NPC). Within the 3 RV species, multiple divergent genotypes encode diverse 2Apro sequences that act differentially on specific Nups. Since only subsets of Phe/Gly motifs, particularly those within Nup62, Nup98, and Nup153, are recognized by transport receptors (karyopherins) when trafficking large molecular cargos through the NPC, the processing preferences of individual 2Apro predict RV genotype-specific targeting of NPC pathways and cargos. To test this idea, transformed HeLa cell lines were created with fluorescent cargos (mCherry) for the importin α/β, transportin 1, and transportin 3 import pathways and the Crm1-mediated export pathway. Live-cell imaging of single cells expressing recombinant RV 2Apro (A16, A45, B04, B14, B52, C02, and C15) showed disruption of each pathway with measurably different efficiencies and reaction rates. The B04 and B52 proteases preferentially targeted Nups in the import pathways, while B04 and C15 proteases were more effective against the export pathway. Virus-type-specific trends were also observed during infection of cells with A16, B04, B14, and B52 viruses or their chimeras, as measured by NF-κB (p65/Rel) translocation into the nucleus and the rates of virus-associated cytopathic effects. This study provides new tools for evaluating the host cell response to RV infections in real time and suggests that differential 2Apro activities explain, in part, strain-dependent host responses and diverse RV disease phenotypes.

IMPORTANCE Genetic variation among human rhinovirus types includes unexpected diversity in the genes encoding viral proteases (2Apro) that help these viruses achieve antihost responses. When the enzyme activities of 7 different 2Apro were measured comparatively in transformed cells programed with fluorescent reporter systems and by quantitative cell imaging, the cellular substrates, particularly in the nuclear pore complex, used by these proteases were indeed attacked at different rates and with different affinities. The importance of this finding is that it provides a mechanistic explanation for how different types (strains) of rhinoviruses may elicit different cell responses that directly or indirectly lead to distinct disease phenotypes.

  • Copyright © 2017 American Society for Microbiology.

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Differential Disruption of Nucleocytoplasmic Trafficking Pathways by Rhinovirus 2A Proteases
Kelly Watters, Bahar Inankur, Jaye C. Gardiner, Jay Warrick, Nathan M. Sherer, John Yin, Ann C. Palmenberg
Journal of Virology Mar 2017, 91 (8) e02472-16; DOI: 10.1128/JVI.02472-16

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Differential Disruption of Nucleocytoplasmic Trafficking Pathways by Rhinovirus 2A Proteases
Kelly Watters, Bahar Inankur, Jaye C. Gardiner, Jay Warrick, Nathan M. Sherer, John Yin, Ann C. Palmenberg
Journal of Virology Mar 2017, 91 (8) e02472-16; DOI: 10.1128/JVI.02472-16
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KEYWORDS

Cysteine Endopeptidases
host-pathogen interactions
Nuclear Pore Complex Proteins
rhinovirus
Viral Proteins
2A
live-cell imaging
nuclear export
nuclear localization
nuclear trafficking
protease
rhinovirus

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