The Hepatitis C virus internal ribosome entry site, or HCV IRES, is an

RNA Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself (non-coding RNA) or by forming a template for the production of proteins (messenger RNA). RNA and deoxyrib ...

structure within the

5'UTR The 5′ untranslated region (also known as 5′ UTR, leader sequence, transcript leader, or leader RNA) is the region of a messenger RNA (mRNA) that is directly upstream from the initiation codon. This region is important for the regulation of ...

of the HCV genome that mediates cap-independent translation initiation. Protein translation of most

eukaryotic The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...

s occurs by a cap-dependent mechanism and requires association of Met-

tRNA Transfer ribonucleic acid (tRNA), formerly referred to as soluble ribonucleic acid (sRNA), is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes). In a cell, it provides the physical link between the gene ...

_i^Met, several eukaryotic initiation factors, and GTP with the 40S

ribosomal Ribosomes () are macromolecular machines, found within all cells, that perform biological protein synthesis (messenger RNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA molecules to fo ...

subunit, recruitment to the

5' cap In molecular biology, the five-prime cap (5′ cap) is a specially altered nucleotide on the 5′ end of some primary transcripts such as precursor messenger RNA. This process, known as mRNA capping, is highly regulated and vital in the creation ...

, and scanning along the 5' UTR to reach to start codon. In contrast, translation of

hepatitis C virus The hepatitis C virus (HCV) is a small (55–65 nm in size), enveloped, positive-sense single-stranded RNA virus of the family ''Flaviviridae''. The hepatitis C virus is the cause of hepatitis C and some cancers such as liver cancer ( hepatoc ...

(HCV) mRNA is initiated by a different mechanism from the usual 5' cap-binding model. This alternate mechanism relies on the direct binding of the 40S ribosomal subunit by the

internal ribosome entry site An internal ribosome entry site, abbreviated IRES, is an RNA element that allows for translation initiation in a cap-independent manner, as part of the greater process of protein synthesis. Initiation of eukaryotic translation nearly always occur ...

(IRES) in the 5' UTR of HCV RNA. The HCV IRES adopts a complex structure, and may differ significantly from IRES elements identified in

picornavirus Picornaviruses are a group of related Viral envelope, nonenveloped RNA viruses which infect vertebrates including fish, mammals, and birds. They are viruses that represent a large family of small, Positive-sense single-stranded RNA virus, positi ...

es. A small number of eukaryotic mRNAs has been shown to be translated by internal ribosome entry.

IRES structure

Nucleotides 1–40 of the HCV mRNA are thought not to contribute to translation, and are rather required for

genomic Genomics is an interdisciplinary field of molecular biology focusing on the structure, function, evolution, mapping, and editing of genomes. A genome is an organism's complete set of DNA, including all of its genes as well as its hierarchical, ...

replication. The remainder 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 independently binds two components of eukaryotic translation initiation machinery, the multiprotein initiation factor

eIF3 Eukaryotic initiation factor 3 (eIF3) is a multiprotein complex that functions during the initiation phase of eukaryotic translation. It is essential for most forms of Eukaryotic translation#Cap-dependent initiation, cap-dependent and Eukaryotic ...

and 40S small ribosomal subunit. Moreover, it binds 40S in such a manner that AUG initiator codon is positioned in the ribosomal P-site, thus no ribosomal scanning is required. Consequently scanning factors

eIF1 Eukaryotic translation initiation factor 1 (eIF1) is a protein that in humans is encoded by the ''EIF1'' gene. It is related to yeast SUI1. eIF1 interacts with the eukaryotic small ( 40S) ribosomal subunit and eIF3, and is a component of the 43S ...

and eIF1A are dispensable for the HCV translation, as are components of the eIF4F complex (

eIF4A The eukaryotic initiation factor-4A (eIF4A) family consists of 3 closely related proteins EIF4A1, EIF4A2, and EIF4A3. These factors are required for the binding of Messenger RNA, mRNA to 40S ribosome, ribosomal subunits. In addition these prot ...

eIF4E Eukaryotic translation initiation factor 4E, also known as eIF4E, is a protein in humans encoded by the ''EIF4E'' gene. eIF4E plays a central role in translation initiation and is involved in regulating protein synthesis. Its activity influences ...

, and

eIF4G Eukaryotic translation initiation factor 4 G (eIF4G) is a protein involved in eukaryotic translation initiation and is a component of the eIF4F cap-binding complex. Orthologs of eIF4G have been studied in multiple species, including humans, yeast ...

) and eIF4B, which are generally required for mRNA binding and unwinding of

. Initiator tRNA is delivered either by

eIF2 Eukaryotic Initiation Factor 2 (eIF2) is a eukaryotic initiation factor. It is required for most forms of eukaryotic translation initiation. eIF2 mediates the binding of tRNAiMet to the ribosome in a GTP-dependent manner. eIF2 is a heterotrimer ...

or, in stress conditions when eIF2 is inactivated, by

eIF2A Eukaryotic translation initiation factor 2A (eIF2A) is a protein that in humans is encoded by the ''EIF2A'' gene. The eIF2A protein is not to be confused with eIF2α, a subunit of the heterotrimeric eIF2 Eukaryotic Initiation Factor 2 (eIF2) is ...

, eIF2D, or possibly eIF5B, a homologue of prokaryotic IF2 protein.

References

External links

* {{Rfam, id=RF00061, name=Hepatitis C virus internal ribosome entry site Cis-regulatory RNA elements Internal ribosome entry site Hepatitis C virus

IRES structure

Mechanism of action

See also

References

Further reading

External links