HCV IRES manipulates the ribosome to promote the switch from translation initiation to elongation

Filbin, Megan E.; Vollmar, Breanna S.; Shi, Dan; Gonen, Tamir; Kieft, Jeffrey S.

doi:10.1038/nsmb.2465

Cited by 63 publications

(77 citation statements)

References 64 publications

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“…The software converts integral band densities of each band into a numerical value. The numerical values were normalized and plotted against sequences (52).…”

Section: Methodsmentioning

confidence: 99%

Recruitment of the 40S Ribosome Subunit to the 3′-Untranslated Region (UTR) of a Viral mRNA, via the eIF4 Complex, Facilitates Cap-independent Translation

Sharma

Kraft²,

Miller

et al. 2015

Journal of Biological Chemistry

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Background: Barley yellow dwarf virus, a positive strand RNA virus, contains a 3Ј-translational enhancer element (BTE). Results: Ribosomes bind the 5Ј-UTR only in the presence of the 3Ј-element. Conclusion:The BTE is the site of initial ribosome recruitment. Significance: Ribosome recruitment to the 3Ј-BTE provides a feedback loop for the switch between translation and transcription of the viral mRNA.

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“…The software converts integral band densities of each band into a numerical value. The numerical values were normalized and plotted against sequences (52).…”

Section: Methodsmentioning

confidence: 99%

Recruitment of the 40S Ribosome Subunit to the 3′-Untranslated Region (UTR) of a Viral mRNA, via the eIF4 Complex, Facilitates Cap-independent Translation

Sharma

Kraft²,

Miller

et al. 2015

Journal of Biological Chemistry

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“…It has been proposed that the IRES must undergo a multi-step rearrangement during binary-complex formation to position domain II [95]; and clearly, for 80S ribosomes to transition into elongation, domain II must be entirely vacated from its E site position to make room for deacyclated initiator tRNA moving from the P site. The structural observations help explain the multipurpose role of domain II during tRNA recruitment and positioning, where it participates in both the formation of productive 48S complexes and the progression of 80S initiation complexes into elongation [82,129,131].…”

Section: (G) Dynamic Rearrangements Within the 80s : Ires Complexmentioning

confidence: 99%

Dynamics of IRES-mediated translation

Johnson

Grosely

Petrov

et al. 2017

Phil. Trans. R. Soc. B

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One contribution of 12 to a theme issue 'Perspectives on the ribosome'. Viral internal ribosome entry sites (IRESs) are unique RNA elements, which use stable and dynamic RNA structures to recruit ribosomes and drive protein synthesis. IRESs overcome the high complexity of the canonical eukaryotic translation initiation pathway, often functioning with a limited set of eukaryotic initiation factors. The simplest types of IRESs are typified by the cricket paralysis virus intergenic region (CrPV IGR) and hepatitis C virus (HCV) IRESs, both of which independently form high-affinity complexes with the small (40S) ribosomal subunit and bypass the molecular processes of cap-binding and scanning. Owing to their simplicity and ribosomal affinity, the CrPV and HCV IRES have been important models for structural and functional studies of the eukaryotic ribosome during initiation, serving as excellent targets for recent technological breakthroughs in cryogenic electron microscopy (cryo-EM) and single-molecule analysis. High-resolution structural models of ribosome : IRES complexes, coupled with dynamics studies, have clarified decades of biochemical research and provided an outline of the conformational and compositional trajectory of the ribosome during initiation. Here we review recent progress in the study of HCV-and CrPV-type IRESs, highlighting important structural and dynamics insights and the synergy between cryo-EM and single-molecule studies.This article is part of the themed issue 'Perspectives on the ribosome'.

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“…In many cases, the IRES mechanism complements the infection strategy of the virus. In the case of the HCV IRES and other IRESs of this type, the IRES can effectively recruit the host translation machinery by directly binding to 40S ribosomal subunits (1,(8)(9)(10)(11)(12). The HCV-ribosome interaction has been shown to require an interaction with ribosomal protein S25 (13) and can also involve the eIF3 complex, which increases the stability of the interaction (14).…”

mentioning

confidence: 99%

Base pairing between hepatitis C virus RNA and 18S rRNA is required for IRES-dependent translation initiation in vivo

Matsuda

Mauro

2014

Proc. Natl. Acad. Sci. U.S.A.

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Degeneracy in eukaryotic translation initiation is evident in the initiation strategies of various viruses. Hepatitis C virus (HCV) provides an exceptional example-translation of the HCV RNA is facilitated by an internal ribosome entry site (IRES) that can autonomously bind a 40S ribosomal subunit and accurately position it at the initiation codon. This binding involves both ribosomal protein and 18S ribosomal RNA (rRNA) interactions. In this study, we evaluate the functional significance of the rRNA interaction and show that HCV IRES activity requires a 3-nt Watson-Crick base-pairing interaction between the apical loop of subdomain IIId in the IRES and helix 26 in 18S rRNA. Mutations of these nucleotides in either RNA dramatically disrupted IRES activity. The activities of the mutated HCV IRESs could be restored by compensatory mutations in the 18S rRNA. The effects of the 18S rRNA mutations appeared to be specific inasmuch as ribosomes containing these mutations did not support translation mediated by the wild-type HCV IRES, but did not block translation mediated by the cap structure or other viral IRESs. The present study provides, to our knowledge, the first functional demonstration of mRNA-rRNA base pairing in mammalian cells. By contrast with other rRNA-binding sites in mRNAs that can enhance translation as independent elements, e.g., the ShineDalgarno sequence in prokaryotes, the rRNA-binding site in the HCV IRES functions as an essential component of a more complex interaction.hepatitis C virus | 18S rRNA | IRES | base pairing | translation H CV is a single-stranded RNA virus that is a major cause of severe liver disease. The RNA genome contains a large ORF and expresses a single polypeptide that is processed into smaller proteins, which are necessary for replication and assembly of viral particles. The RNA genome is uncapped, and translation does not require the eukaryotic initiation factor 4F (eIF4F) complex (1), which mediates cap-dependent translation. Instead, translation is facilitated by an internal ribosome entry site (IRES) located in the 5′ nontranslated region (2, 3). Inasmuch as the production of all HCV proteins requires the HCV IRES, the HCV IRES is a therapeutic target (4).IRESs encompass a variety of initiation mechanisms and have been extensively studied in viruses, which often exploit the translation capabilities of the host for their own use (5-7). In many cases, the IRES mechanism complements the infection strategy of the virus. In the case of the HCV IRES and other IRESs of this type, the IRES can effectively recruit the host translation machinery by directly binding to 40S ribosomal subunits (1,(8)(9)(10)(11)(12). The HCV-ribosome interaction has been shown to require an interaction with ribosomal protein S25 (13) and can also involve the eIF3 complex, which increases the stability of the interaction (14). In the presence of ternary complex, which contains the initiator Met-tRNA, a preinitiation complex can assemble at the start site.Various studies have investigated the binding of ...

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HCV IRES manipulates the ribosome to promote the switch from translation initiation to elongation

Cited by 63 publications

References 64 publications

Recruitment of the 40S Ribosome Subunit to the 3′-Untranslated Region (UTR) of a Viral mRNA, via the eIF4 Complex, Facilitates Cap-independent Translation

Recruitment of the 40S Ribosome Subunit to the 3′-Untranslated Region (UTR) of a Viral mRNA, via the eIF4 Complex, Facilitates Cap-independent Translation

Dynamics of IRES-mediated translation

Base pairing between hepatitis C virus RNA and 18S rRNA is required for IRES-dependent translation initiation in vivo

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