Protein Synthesis in Eukaryotes: IRES‐mediated Internal Initiation

Nahum Sonenberg, McGill University, Quebec, Canada

Published online: January 2006

DOI: 10.1038/npg.els.0003869

Internal initiation is an alternative mechanism to the general pathway of translation initiation in eukaryotes and involves the internal binding of ribosomes to a specific sequence in the messenger ribonucleic acid (mRNA) called the internal ribosome entry site (IRES). The mRNA 5¢ cap structure and a cap-binding protein, eukaryotic initiation factor (eIF) 4E, play a key role in the canonical mechanism of translation initiation. However, internal initiation is independent of the cap structure and eIF4E. IRES-mediated translation initiation has been documented for viral and cellular mRNAs, and functions during mitosis and stress conditions, such as apoptosis and hypoxia.

Keywords: protein synthesis; initiation factors; internal initiation; IRES (internal ribosome entry site); picornaviruses

Figure 1. Comparison of different models of IRES-mediated cap-independent translation with cap-dependent translation. (a) Cap-dependent translation. Eukaryotic initiation factor (eIF) 4F through its cap-binding subunit, eIF4E, binds to the mRNA 5¢ cap structure. eIF4A is an RNA helicase and eIF4G is a scaffolding protein that bridges the mRNA to the 40S ribosome (associated with the ternary complex: eIF2–Met transfer RNA (tRNA)–guanosine triphosphate (GTP)) through the multisubunit factor eIF3. ORF, open reading frame. (b) IRES-mediated cap-independent translation. The general pathway (top) is used by most of the viral and cellular mRNAs, which initiate by an IRES-mediated mechanism. All the initiation factors that are required for cap-dependent translation are also required for general IRES-mediated translation, with the exception of eIF4E, which is not required for IRES-mediated translation, even for capped cellular mRNAs. eIF4G binds directly to the IRES, and recruits the eIF3–40S ribosome complex to the mRNA. Some mRNAs, such as those of picornaviruses, do not contain a cap structure at their 5¢ end. The Hepatitis C virus (HCV) pathway (middle) is used by HCV and ‘Classical swine fever virus’ (CSFV). It differs from the general pathway of IRES-mediated translation by its complete independence of eIF4 initiation factors (eIF4A, eIF4B, eIF4E and eIF4G). The 40S subunit containing the ternary complex (eIF2–Met-tRNA–GTP) binds directly at the IRES, which encompasses the AUG initiation codon. The 5¢ end of these mRNAs is not capped. N is any nucleotide. The final pathway is used by ‘Cricket paralysis virus’ and ‘Plautia stali intestinal virus.’ Translation does not start with a methionine. Translation initiation does not require any of the known initiation factors or initiator tRNA. Instead, the mRNA forms a pseudoknot whereby base pairing between the upstream sequences and the triplet sequence in the P site is formed. VPg (viral protein genome-linked) is a small protein linked to the 5¢ end of the genomic RNA.
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 References
    Chen C-Y and Sarnow P (1995) Initiation of protein synthesis by the eukaryotic translational apparatus on circular RNAs. Science 268: 415–417.
    Jang SK, Krausslich HG, Nicklin MJH et al. (1988) A segment of the 5¢ non-translated region of encephalomyocarditis virus RNA directs internal entry of ribosomes during in vitro translation. Journal of Virology 62: 2636–2643.
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 Further Reading
    book Belsham GJ and Jackson RJ (2000) "Translation initiation on picornavirus RNAs". In: Sonenberg N, Hershey JWB and Mathews MB (eds) Translational Control of Gene Expression, pp. 869–900. Plainview, New York: Cold Spring Harbor Press.
    book Carter MS, Kuhn KM and Sarnow P (2000) "Cellular internal ribosome entry site elements and the use of cDNA microarrays in their investigation". In: Sonenberg N, Hershey JWB and Matthews MB (eds) Translational Control of Gene Expression, pp. 615–635. Plainview, New York: Cold Spring Harbor Press.
    Gingras AC, Raught B and Sonenberg N (1999) eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annual Review of Biochemistry 68: 913–963.
    book Hershey JWB and Merrick WC (2000) "The pathway and mechanism of eukaryotic protein synthesis". In: Sonenberg N, Hershey JWB and Mathews MB (eds) Translational Control of Gene Expression, pp. 33–88. Plainview, New York: Cold Spring Harbor Press.
    RajBhandary UL (2000) More surprises in translation: initiation without the initiator tRNA. Proceedings of the National Academy of Sciences of the USA 97: 1325–1327.
    Hellen C and Sarnow P (2001) Internal ribosome entry sites in eukaryotic mRNA molecules. Genes and Development 15: 1593–1612.
    Kamar, AA and Hatzozlon, M (2005) Internal ribosome entry sites in cellular mRNAs: mystery of their existence (2005). Journal of Biological Chemistry 280: 23425–23428.

Related Sub-Topics:

Nucleic Acid Structure | Translation and Protein synthesis | Translation of RNA | Biomolecular Interactions | Nucleic Acids: Structure, Function, Metabolism
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Article Title: Protein Synthesis in Eukaryotes: IRES‐mediated Internal Initiation
 
How to Cite close
Sonenberg, Nahum(Jan 2006) Protein Synthesis in Eukaryotes: IRES‐mediated Internal Initiation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0003869]