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

RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...

structure within the 5'UTR of the HCV genome that mediates cap-independent translation initiation. Protein translation of most

eukaryotic Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...

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 RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA) is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes), that serves as the physical link between the mRNA and the amino ac ...

_i^Met, several

eukaryotic initiation factors Eukaryotic initiation factors (eIFs) are proteins or protein complexes involved in the initiation phase of eukaryotic translation. These proteins help stabilize the formation of ribosomal preinitiation complexes around the start codon and are an i ...

, and GTP with the 40S

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

subunit, recruitment to the 5' cap, 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 ( hepato ...

(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. In eukaryotic translation, initiation typically occurs at t ...

(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 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 viruses with a 30 nm ...

es. A small number of eukaryotic mRNA have 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 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, three-dim ...

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 t ...

and

40S The eukaryotic small ribosomal subunit (40S) is the smaller subunit of the eukaryotic 80S ribosomes, with the other major component being the large ribosomal subunit (60S). The "40S" and "60S" names originate from the convention that ribosomal pa ...

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 and

eIF1A Eukaryotic translation initiation factor 1A, X-chromosomal (eIF1A) is a protein that in humans is encoded by the ''EIF1AX'' gene. This gene encodes an essential eukaryotic translation initiation factor. The protein is a component of the 43S pre-in ...

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 mRNA to 40S ribosomal subunits. In addition these proteins are helicases that f ...

eIF4E Eukaryotic translation initiation factor 4E, also known as eIF4E, is a protein that in humans is encoded by the ''EIF4E'' gene. Structure and function Most eukaryotic cellular mRNAs are blocked at their 5'-ends with the 7-methyl-guanosine fi ...

, 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 Eukaryotic translation initiation factor 4B is a protein that in humans is encoded by the ''EIF4B'' gene. Interactions eIF4B has been shown to interact with and stimulate the activity of eIF4A and bind to the eIF3 complex through the eIF3A subu ...

, which are generally required for mRNA binding and unwinding of 5'UTR. Initiator tRNA is delivered either by

eIF2 Eukaryotic Initiation Factor 2 (eIF2) is an 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 c ...

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 complex. Instead, eIF2A functions by a sepa ...

, eIF2D, or possibly

eIF5B Eukaryotic translation initiation factor 5B is a protein that in humans is encoded by the ''EIF5B'' gene. Accurate initiation of translation in eukaryotes is complex and requires many factors, some of which are composed of multiple subunits. The ...

, 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