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EMBO J ; 20(23): 6899-908, 2001 Dec 03.
Article in English | MEDLINE | ID: mdl-11726525

ABSTRACT

Translation initiation of the picornavirus genome is regulated by an internal ribosome entry site (IRES). The IRES of a neurovirulent picornavirus, the GDVII strain of Theiler's murine encephalomyelitis virus, requires polypyrimidine tract-binding protein (PTB) for its function. Although neural cells are deficient in PTB, they express a neural-specific homologue of PTB (nPTB). We now show that nPTB and PTB bind similarly to multiple sites in the GDVII IRES, rendering it competent for efficient translation initiation. Mutation of a PTB or nPTB site results in a more prominent decrease in nPTB than PTB binding, a decrease in activity of nPTB compared with PTB in promoting translation initiation, and attenuation of the neurovirulence of the virus without a marked effect on virus growth in non-neural cells. The addition of a second-site mutation in the mutant IRES generates a new PTB (nPTB) binding site, and restores nPTB binding, translation initiation and neurovirulence. We conclude that the tissue-specific expression and differential RNA-binding properties of PTB and nPTB are important determinants of cell-specific translational control and viral neurovirulence.


Subject(s)
RNA, Viral/metabolism , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Ribonucleoproteins/genetics , Ribonucleoproteins/metabolism , Viruses/pathogenicity , Animals , Base Sequence , Binding Sites , Cell Line , Cricetinae , Mice , Molecular Sequence Data , Mutation , Plasmids/metabolism , Polypyrimidine Tract-Binding Protein , Protein Binding , Protein Biosynthesis , RNA/metabolism , Ribosomes/chemistry , Transfection
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