Nucleoporin Phosphorylation Triggered by the Encephalomyocarditis Virus Leader Protein Is Mediated by Mitogen-Activated Protein Kinases
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Cardioviruses disrupt nucleocytoplasmic transport through the activity of their leader (L) protein. We have shown that hyperphosphorylation of nuclear pore proteins (nucleoporins or Nups), including Nup62, Nup153, and Nup214, is central to this L protein function and requires one or more cytosolic kinases. In this study, potential cellular enzymes involved in encephalomyocarditis virus (EMCV) L-directed Nup phosphorylation were screened with a panel of specific, cell-permeating kinase inhibitors. Extracellular signal-regulated receptor kinase (ERK) and p38 mitogen-activated protein kinase inhibitors (U0126 and SB203580) were sufficient to block Nup hyperphosphorylation in EMCV-infected or L-expressing cells. Recombinant L alone, in the absence of infection, triggered activation of ERK and p38, independent of their upstream signaling cascades. Conserved residues within the L zinc finger (Cys 19 ) and acidic domain (Asp 48 , 51 , 52 , 55 ) were essential for this activation and for the phosphorylation of Nups, suggesting that the phenomena are linked. Analysis of the hyperphosphorylated Nup species revealed only phosphoserine and phosphothreonine residues. The sizes of the tryptic phosphopeptides derived from Nup62 were compatible with sites in the Phe/Gly repeat domain which display common consensus sequences for ERK and p38 substrates. The results provide strong evidence that ERK and p38 are the probable effector kinases required for L-dependent inhibition of nuclear trafficking.
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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 [152]
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- Authors
- Porter, F. W., Brown, B., & Palmenberg, A. C.
- Affiliations
- University of Wisconsin–Madison (US)
- ORCID
- Palmenberg, Ann C.
- Venue
- Journal of Virology
- Publisher
- American Society for Microbiology
- Published
- 2010-12-15
- Volume
- 84
- Issue
- 24
- Pages
- 12538-12548
- ISSN
- 0022-538X (ISSN-L)
- 1098-5514
- PMC
- PMC3004318
- OpenAlex
- W2161664101
- Cited by
- 57
- References
- 53
- Citations by year
- 2026: 1 · 2024: 5 · 2023: 1 · 2022: 8 · 2021: 2 · 2020: 3 · 2019: 4 · 2018: 5 · 2017: 3 · 2015: 4 · 2014: 7 · 2013: 5 · 2012: 8
- FWCI
- 1.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- 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, nucleoporins, Nup62, Nup153, Nup214, ERK, p38 MAPK, zinc finger, acidic domain, phosphopeptides, kinase inhibitors
- MeSH terms
- Butadienes, Encephalomyocarditis virus, Enzyme Inhibitors, HeLa Cells, Humans, Imidazoles, Nitriles, Phosphopeptides, Phosphorylation, Pyridines, Protein Biosynthesis, Viral Proteins, Blotting, Western, Cardiovirus Infections, Mitogen-Activated Protein Kinase 1, Nuclear Pore Complex Proteins, p38 Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase 3
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