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PMID: 16809299 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The double-stranded RNA binding protein 76:NF45 heterodimer inhibits translation initiation at the rhinovirus type 2 internal ribosome entry site.

Journal of virology ·Vol. 80 ·No. 14 ·2006-07-00 ·Pages 6936-42

Merrill MK, Gromeier M

Abstract

Poliovirus (PV) plus-strand RNA genomes initiate translation in a cap-independent manner via an internal ribosome entry site (IRES) in their 5' untranslated region. Viral translation is codetermined by cellular IRES trans-acting factors, which can influence viral propagation in a cell-type-specific manner. Engineering of a poliovirus recombinant devoid of neuropathogenic properties but highly lytic in malignant glioma cells was accomplished by exchange of the cognate poliovirus IRES with its counterpart from human rhinovirus type 2 (HRV2), generating PV-RIPO. Neuroblast:glioma heterokaryon analyses revealed that loss of neurovirulence is due to trans-dominant repression of PV-RIPO propagation in neuronal cells. The double-stranded RNA binding protein 76 (DRBP76) was previously identified to bind to the HRV2 IRES in neuronal cells and to inhibit PV-RIPO translation and propagation (M. Merrill, E. Dobrikova, and M. Gromeier, J. Virol. 80:3347-3356, 2006). The results of size exclusion chromatography indicate that DRBP76 heterodimerizes with nuclear factor of activated T cells, 45 kDa (NF45), in neuronal but not in glioma cells. The DRBP76:NF45 heterodimer binds to the HRV2 IRES in neuronal but not in glioma cells. Ribosomal profile analyses show that the heterodimer preferentially associates with the translation apparatus in neuronal cells and arrests translation at the HRV2 IRES, preventing PV-RIPO RNA assembly into polysomes. Results of this study suggest that the DRBP76:NF45 heterodimer selectively blocks HRV2 IRES-driven translation initiation in neuron-derived cells.

MeSH Terms
5' Untranslated Regions/metabolism Cell Line, Tumor Chromatography, Gel Dimerization Glioma/metabolism,virology Humans Hybridomas Neurons/metabolism,virology Nuclear Factor 45 Protein/metabolism Organ Specificity Polyribosomes/metabolism Protein Binding Protein Biosynthesis RNA, Double-Stranded/metabolism RNA, Viral/metabolism RNA-Binding Proteins/metabolism Rhinovirus/metabolism,pathogenicity
Chemicals
5' Untranslated Regions ILF2 protein, human Nuclear Factor 45 Protein RNA, Double-Stranded RNA, Viral RNA-Binding Proteins
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Merrill Melinda K
Department of Molecular Genetics & Microbiology, Duke University Medical Center, Box 3020, Durham, NC 27710, USA.
Gromeier Matthias
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Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/JVI.00243-06
Published
2006-07-00
Pages
6936-42
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC1489066
Subset
IM
Grants
NINDS NIH HHS · NS20023 · United States
NINDS NIH HHS · P50 NS020023 · United States
NCI NIH HHS · CA87537 · United States
NCI NIH HHS · R55 CA087537 · United States
NCI NIH HHS · R01 CA087537 · United States
External Links
PubMed source DOI: 10.1128/JVI.00243-06 PMC Full Text View journal details
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