Hepatitis C virus internal ribosome entry site

Protein translation of most eukaryotic mRNAs requires association of Met-tRNA, several eukaryotic initiation factors, and GTP with the 40S ribosomal subunit. The ribosome can only bind the capped mRNA after binding the initiator tRNA. Translation of hepatitis C virus (HCV) mRNA is initiated by a different mechanism from the usual 5' cap-binding model. [cite journal | last = Lytle | first = JR | coauthors = Wu L, Robertson HD | year = 2002 | title = Domains on the hepatitis C virus internal ribosome entry site for 40s subunit binding | journal = RNA | volume = 8 | pages = 1045–1055 | pmid = 12212848 | doi = 10.1017/S1355838202029965] This alternate mechanism relies on the direct binding of the 40S ribosomal subunit by the internal ribosome entry site (IRES) in the 5' UTR of HCV RNA. HCV IRES adopts a complex structure, and may differ significantly from IRES elements identified in picornaviruses. A small number of eukaryotic mRNA have been shown to be translated by internal ribosome entry. [cite journal | last = Beales | first = LP | coauthors = Rowlands DJ, Holzenburg A | year = 2001 | title = The internal ribosome entry site (IRES) of hepatitis C virus visualized by electron microscopy | journal = RNA | volume = 7 | pages = 661–670 | pmid = 11350030 | doi = 10.1017/S1355838201001406] [cite journal | last = Gallego | first = J | coauthors = Varani G | year = 2002 | title = The hepatitis C virus internal ribosome-entry site: a new target for antiviral research | journal = Biochem Soc Trans | volume = 30 | pages = 140–145 | pmid = 12023841 | doi = 10.1042/BST0300140]

IRES structure

Nucleotides 1-40 of the HCV mRNA are thought not to contribute to translation, and are rather required for genomic RNA replication. The reminder of the HCV 5'-UTR consists of three domains, namely domains II-IV (domain I is located on the 5'-end of the mRNA).

Mechanism of action

HCV IRES binds independently two components of eukaryotic translation initiation machinery, protein eIF3 and 40S small ribosome subunit. Moreover, it bins 40S in such a manner that AUG initiator codon is positioned in ribosomal P-site, thus no ribosomal scanning is required. Consequently scanning factors eIF1 and eIF1A are dispensable for the HCV translation. And so are factors generally required for mRNA binding and unwinding of 5'-UTR, eIF4A, eIF4B and eIF4F.Initiator tRNA is brought then either by eIF2 or, in stress conditions when eIF2 is inactivated, by eIF5B, homologoue of prokaryotic IF2 protein.

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