Autogenous translational inhibition of core protein: implication for switch from translation to RNA replication in hepatitis C virus.
Positive-stranded viruses use the genomic RNA as a common template for translation and RNA replication which proceed in inverse direction; a certain regulatory mechanism for translation control is probably required to coordinate these two antagonistic processes. Hepatitis C virus (HCV) core protein is a good candidate that might play a role in such a regulation. In this study, we further investigated whether HCV core protein modulates internal ribosome entry site (IRES)-directed translation. The inclusion of the core-coding sequence significantly suppressed translation initiated by HCV IRES in monocistronic and bicistronic reporter systems. The region mainly responsible for this inhibition was mapped to nt 441-473 of the core-coding sequence. This suppression was eliminated by frameshift mutations introduced into this region, suggesting that it is the core protein expressed in cis, rather than the core-coding nucleotide sequence that negatively modulates the efficiency of HCV IRES-dependent translation. Furthermore, the core protein provided in trans also specifically decreased the IRES activity in directing cap-independent translation both in transfected cells and in cell-free translation study. Consistently, a gel mobility shift assay showed a specific interaction between the core protein and HCV IRES-containing RNA transcript. These findings suggest that HCV core protein may down-regulate the cap-independent translation as a regulatory mechanism required for initiation of transcription.
Zhang
Jing
J
Research and Development Center, FUSO Pharmaceutical Industries, Ltd., 2-3-30 Morinomiya, Joto-ku, Osaka 536-8523, Japan. j-zhang@fuso-pharm.co.jp
Yamada
Osamu
O
Yoshida
Hiroshi
H
Iwai
Takahiro
T
Araki
Hiromasa
H
D020121:5' Untranslated Regions / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D016174:Hepacivirus / Q000235:genetics*; D014176:Protein Biosynthesis; D012367:RNA, Viral / Q000096:biosynthesis*; D014758:Viral Core Proteins / Q000502:physiology*
D020121:5' Untranslated Regions; D012367:RNA, Viral; D014758:Viral Core Proteins