title: Cell-specific proteins regulate viral RNA translation and virus-induced disease.
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.
authors.affiliation: Department of Neurology, University of Chicago Medical Center, Chicago, IL 60637, USA. epilipen@neurology.bsd.uchicago.edu
authors.forename: E V
authors.initials: EV
authors.lastname: Pilipenko
authors.forename: E G
authors.initials: EG
authors.lastname: Viktorova
authors.forename: S T
authors.initials: ST
authors.lastname: Guest
authors.forename: V I
authors.initials: VI
authors.lastname: Agol
authors.forename: R P
authors.initials: RP
authors.lastname: Roos
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D006224:Cricetinae; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D038941:Polypyrimidine Tract-Binding Protein; D011485:Protein Binding; D014176:Protein Biosynthesis; D012313:RNA / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D012261:Ribonucleoproteins / Q000235:genetics* / Q000378:metabolism*; D012270:Ribosomes / Q000737:chemistry; D014162:Transfection; D014780:Viruses / Q000472:pathogenicity*
chemical_list: D012367:RNA, Viral; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; D038941:Polypyrimidine Tract-Binding Protein; D012313:RNA