Leader-Induced Phosphorylation of Nucleoporins Correlates with Nuclear Trafficking Inhibition by Cardioviruses

Porter, Frederick W.; Palmenberg, Ann C.

doi:10.1128/jvi.01752-08

Cited by 99Nuclear Structure and FunctionViral Infections and Immunology ResearchVirology and Viral Diseases

Leader-Induced Phosphorylation of Nucleoporins Correlates with Nuclear Trafficking Inhibition by Cardioviruses

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Porter, Frederick W., Palmenberg, Ann C.·2009·Journal of Virology

DOI 10.1128/jvi.01752-08PMC PMC2643766

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Abstract

Picornaviruses disrupt nucleocytoplasmic trafficking pathways during infection. Poliovirus and rhinovirus inhibit nuclear protein import/export through a series of 2A protease-dependent cleavages within nuclear pore proteins (nucleoporins [Nups]), including Nup62, Nup98, and Nup153. Cardioviruses lack the same protease and instead affect trafficking inhibition through an activity mapped to their leader (L) protein, a 67- to 76-amino acid (aa) polypeptide with no known enzymatic activity. We have shown that L from encephalomyocarditis virus (EMCV) binds and inhibits the activity of Ran-GTPase, a key regulator of nucleocytoplasmic transport. We now report that recombinant EMCV L triggers the unregulated efflux of protein cargo from preloaded HeLa cell nuclei in cell-free reactions dependent upon Xenopus egg cytosol or HeLa cell-derived cytosol. Recombinant L was the only viral protein necessary for this activity or for nuclear protein import inhibition. Mutational disruption of the L protein zinc finger domain (C 19 A) abrogated the inhibitory activity for both import and efflux in cell extracts, but mutations in the C-terminal acidic domain of L (aa 37 to 61) did not. Notably, HeLa cell nuclei treated with L, or those from EMCV-infected cells, showed reproducibly altered patterns of nucleoporin phosphorylation. Nup62, Nup153, and Nup214 each became hyperphosphorylated in an L-dependent manner. Staurosporine, a broad-spectrum kinase inhibitor, blocked this phosphorylation and rescued nuclear import/export activity from L-dependent inhibition. Therefore, cardioviruses target the same group of nucleoporins as enteroviruses, but the effector mechanism triggered by L (or L-Ran complexes) involves a unique cytosol-dependent phosphorylation cascade rather than proteolysis.

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EMCV L protein appears to suppress interferon production and impair nucleo-cytoplasmic trafficking through the binding of Ran-GTPase and through phosphorylation and inactivation of nucleoporins.
“Even if EMCV L protein is devoid of any known enzymatic activity, in contrast to that of aphtovirus, it appears to suppress interferon production149 and impair nucleo-cytoplasmic trafficking through the binding of Ran-GTPase (Ras-related nuclear -GTPase required for the RNA and protein translocation through the nuclear pores) and through phosphorylation and inactivation of nucleoporins.150-154”
From The encephalomyocarditis virus (2012) · cites this paper as [153]

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Keywords: Nucleocytoplasmic trafficking inhibition
Ciomperlik, J. J., Basta, H. A., A, A. C. P., Protein, L., & Acid, O. (2015)
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Authors: Porter, F. W., & Palmenberg, A. C.
Affiliations: University of Wisconsin–Madison (US)
ORCID: Palmenberg, Ann C.
Venue: Journal of Virology
Publisher: American Society for Microbiology
Published: 2009-02-15
Volume: 83
Issue: 4
Pages: 1941-1951
ISSN: 0022-538X (ISSN-L)
1098-5514
DOI: 10.1128/jvi.01752-08
PMC: PMC2643766
OpenAlex: W2134535288
Cited by: 96
References: 38
Citations by year: 2026: 1 · 2025: 4 · 2024: 5 · 2023: 1 · 2022: 5 · 2021: 5 · 2020: 3 · 2019: 7 · 2018: 4 · 2017: 2 · 2016: 4 · 2015: 8 · 2014: 11 · 2013: 9 · 2012: 9
FWCI: 2.61
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Journal of Virology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (AI017331)
National Institute of Allergy and Infectious Diseases (R56AI017331, R01AI017331, AI017331)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Viral Infections and Immunology Research
Health Sciences › Medicine › Epidemiology › Virology and Viral Diseases
Keywords: encephalomyocarditis virus, Ran GTPase, Nup62, Nup153, Nup214, nuclear import inhibition, nuclear export, zinc finger, staurosporine, picornavirus
MeSH terms: Animals, Cell Nucleus, Cytoplasm, Encephalomyocarditis virus, HeLa Cells, Humans, Mutation, Ovum, Phosphorylation, Viral Proteins, Xenopus, Protein Transport, Nuclear Pore Complex Proteins

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Leader-Induced Phosphorylation of Nucleoporins Correlates with Nuclear Trafficking Inhibition by Cardioviruses

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