Ribosome shunting

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Ribosome shunting is a mechanism of translation initiation in which ribosomes bypass, or "shunt over", parts of the 5' untranslated region to reach the start codon. However, a benefit of ribosomal shunting is that it can translate backwards allowing more information to be stored than usual in an mRNA molecule. Some viral RNAs have been shown to use ribosome shunting as a more efficient form of translation during certain stages of viral life cycle or when translation initiation factors are scarce (e.g. cleavage by viral proteases). Some viruses known to use this mechanism include adenovirus, Sendai virus, human papillomavirus, duck hepatitis B pararetrovirus, rice tungro bacilliform viruses, and cauliflower mosaic virus. In these viruses the ribosome is directly translocated from the upstream initiation complex to the start codon (AUG) without the need to unwind RNA secondary structures. [1]

Contents

Ribosome shunting in Cauliflower mosaic virus

Translation of Cauliflower mosaic virus (CaMV) 35S RNA is initiated by a ribosome shunt. [2] The 35S RNA of CaMV contains a ~600 nucleotide leader sequence which contains 7-9 short open reading frames (sORFs) depending on the strain. This long leader sequence has the potential to form an extensive complex stem-loop structure, which is an inhibitory element for expression of following ORFs. However, translation of ORFs downstream of the CaMV 35S RNA leader has been commonly observed. [3] Ribosome shunting model indicates with the collaboration of initiation factors, ribosomes start scanning from capped 5’-end and scans for a short distance until it hits the first sORF. [4] The hairpin structure formed by leader brings the first long ORF into the close spatial vicinity of a 5’-proximal sORF. [5] After read through sORF A, the 80S scanning ribosome disassembles at the stop codon, which is the shunt take-off site. The 40S ribosomal subunits keep combining with RNA, and bypass the strong stem-loop structural element, land at the shunt acceptor site, resume scanning and reinitiate at the first long ORF. 5’-proximal sORF A and the stem-loop structure itself are two essential elements for CaMV shunting [5]. sORFs with 2-15 codons, and 5-10 nucleotides between sORF stop codon and the base of the stem structure are optimal for ribosome shunting, while the minimal (start-stop) ORF does not promote shunting. [6]

Ribosome shunting in Rice tungro bacilliform pararetrovirus

Ribosome shunting process was first discovered in CaMV in 1993, and then was reported in Rice tungro bacilliform virus (RTBV) in 1996. [7] The mechanism of ribosome shunting in RTBV resembles that in CaMV: it also requires the first short ORF as well as a following strong secondary structure. Swapping of the conserved shunt elements between CaMV and RTBV revealed the importance of nucleotide composition of the landing sequence for efficient shunting, indicating that the mechanism of ribosome shunting is evolutionary conserved in plant pararetroviruses. [8]

Ribosome shunting in Sendai virus

Sendai virus Y proteins are initiated by ribosome shunting. Among 8 primary translation products of Sendai virus P/C mRNA, leaky scanning accounts for translation of protein C’, P, and C proteins, while expression of protein Y1 and Y2 is initiated via a ribosomal shunt discontinuous scanning. Scanning complex enters 5’ cap and scan ~50 nucleotides of 5’ UTR, and then is transferred to an acceptor site at or close the Y initiation codons. In the case of Sendai virus, no specific donor site sequences are required. [9] [10]

Ribosome shunt in Adenovirus

Ribosome shunting is observed during expression of late adenovirus mRNAs. Late adenovirus mRNAs contains a 5’ tripartite leader, a highly conserved 200-nucleotide NTR with a 25- to 44- nucleotide unstructured 5’ conformation followed by a complex group of stable hairpin structure, which confers preferential translation by reducing the requirement for the eIF-4F (cap-binding protein complex), which is inactivated by adenovirus to interfere with cellular protein translation. When eIF4E is abundant, the subunit binds to the 5' cap on mRNAs, forming an eIF4 complex leading to shunting; however, when eIF4E is altered or deactivated during late adenovirus infection of heat shock, the tripartite leader exclusively and efficiently directs initiation by shunting. [11]

While Adenovirus required tyrosine kinase to infect the cells without it by disrupting the cap-initiation complex known as the tripartite leader. It disrupts the process via ribosome shunting, in tyrosine phosphorylation. There are two key sites for the binding of the ribosome. In translating viral mRNA and suppressing the translation while being capped by ribosome shunting process. [12] In the case of adenovirus late mRNA and hsp70 mRNA, instead of recognition of stop codon of first short ORF, pausing of translation is caused by scanning ribosome with three conserved sequences that are complementary to the 3’ hairpin of 18S ribosomal RNA. [13] The mechanism for ribosome shunt involves the larger subunit binding upstream of the start codon. The polymerase is then able to leapfrog using protein binding and a power stroke to bypass the start codon on the coding mRNA. The tripate is then inserted into the parent strand to create a new binding site for further replication.

Related Research Articles

<span class="mw-page-title-main">Translation (biology)</span> Cellular process of protein synthesis

In biology, translation is the process in living cells in which proteins are produced using RNA molecules as templates. The generated protein is a sequence of amino acids. This sequence is determined by the sequence of nucleotides in the RNA. The nucleotides are considered three at a time. Each such triple results in addition of one specific amino acid to the protein being generated. The matching from nucleotide triple to amino acid is called the genetic code. The translation is performed by a large complex of functional RNA and proteins called ribosomes. The entire process is called gene expression.

Cauliflower mosaic virus (CaMV) is a member of the genus Caulimovirus, one of the six genera in the family Caulimoviridae, which are pararetroviruses that infect plants. Pararetroviruses replicate through reverse transcription just like retroviruses, but the viral particles contain DNA instead of RNA.

The 5′ untranslated region is the region of a messenger RNA (mRNA) that is directly upstream from the initiation codon. This region is important for the regulation of translation of a transcript by differing mechanisms in viruses, prokaryotes and eukaryotes. While called untranslated, the 5′ UTR or a portion of it is sometimes translated into a protein product. This product can then regulate the translation of the main coding sequence of the mRNA. In many organisms, however, the 5′ UTR is completely untranslated, instead forming a complex secondary structure to regulate translation.

The Shine–Dalgarno (SD) sequence is a ribosomal binding site in bacterial and archaeal messenger RNA, generally located around 8 bases upstream of the start codon AUG. The RNA sequence helps recruit the ribosome to the messenger RNA (mRNA) to initiate protein synthesis by aligning the ribosome with the start codon. Once recruited, tRNA may add amino acids in sequence as dictated by the codons, moving downstream from the translational start 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 the 5' end of mRNA molecules, since 5' cap recognition is required for the assembly of the initiation complex. The location for IRES elements is often in the 5'UTR, but can also occur elsewhere in mRNAs.

Bacterial translation is the process by which messenger RNA is translated into proteins in bacteria.

Eukaryotic translation is the biological process by which messenger RNA is translated into proteins in eukaryotes. It consists of four phases: initiation, elongation, termination, and recapping.

The Kozak consensus sequence is a nucleic acid motif that functions as the protein translation initiation site in most eukaryotic mRNA transcripts. Regarded as the optimum sequence for initiating translation in eukaryotes, the sequence is an integral aspect of protein regulation and overall cellular health as well as having implications in human disease. It ensures that a protein is correctly translated from the genetic message, mediating ribosome assembly and translation initiation. A wrong start site can result in non-functional proteins. As it has become more studied, expansions of the nucleotide sequence, bases of importance, and notable exceptions have arisen. The sequence was named after the scientist who discovered it, Marilyn Kozak. Kozak discovered the sequence through a detailed analysis of DNA genomic sequences.

Initiation factors are proteins that bind to the small subunit of the ribosome during the initiation of translation, a part of protein biosynthesis.

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 important input for post-transcription gene regulation. Several initiation factors form a complex with the small 40S ribosomal subunit and Met-tRNAiMet called the 43S preinitiation complex. Additional factors of the eIF4F complex recruit the 43S PIC to the five-prime cap structure of the mRNA, from which the 43S particle scans 5'-->3' along the mRNA to reach an AUG start codon. Recognition of the start codon by the Met-tRNAiMet promotes gated phosphate and eIF1 release to form the 48S preinitiation complex, followed by large 60S ribosomal subunit recruitment to form the 80S ribosome. There exist many more eukaryotic initiation factors than prokaryotic initiation factors, reflecting the greater biological complexity of eukaryotic translation. There are at least twelve eukaryotic initiation factors, composed of many more polypeptides, and these are described below.

<span class="mw-page-title-main">Hepatitis A virus internal ribosome entry site (IRES)</span>

This family represents the internal ribosome entry site (IRES) of the hepatitis A virus. HAV IRES is a 450 nucleotide long sequence located in the 735 nt long 5’ UTR of Hepatitis A viral RNA genome. IRES elements allow cap and end-independent translation of mRNA in the host cell. The IRES achieves this by mediating the internal initiation of translation by recruiting a ribosomal 40S pre-initiation complex directly to the initiation codon and eliminates the requirement for eukaryotic initiation factor, eIF4F.

<span class="mw-page-title-main">Hepatitis C virus internal ribosome entry site</span>

The Hepatitis C virus internal ribosome entry site, or HCV IRES, is an RNA structure within the 5'UTR of the HCV genome that mediates cap-independent translation initiation.

<span class="mw-page-title-main">Tobamovirus internal ribosome entry site (IRES)</span>

The Tobamovirus internal ribosome entry site (IRES) is an element that allows cap and end-independent translation of mRNA in the host cell. The IRES achieves this by mediating the internal initiation of translation by recruiting a ribosomal 43S pre-initiation complex directly to the initiation codon and eliminates the requirement for the eukaryotic initiation factor, eIF4F.

A ribosome binding site, or ribosomal binding site (RBS), is a sequence of nucleotides upstream of the start codon of an mRNA transcript that is responsible for the recruitment of a ribosome during the initiation of translation. Mostly, RBS refers to bacterial sequences, although internal ribosome entry sites (IRES) have been described in mRNAs of eukaryotic cells or viruses that infect eukaryotes. Ribosome recruitment in eukaryotes is generally mediated by the 5' cap present on eukaryotic mRNAs.

Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during translation that results in the production of multiple, unique proteins from a single mRNA. The process can be programmed by the nucleotide sequence of the mRNA and is sometimes affected by the secondary, 3-dimensional mRNA structure. It has been described mainly in viruses, retrotransposons and bacterial insertion elements, and also in some cellular genes.

<i>Sobemovirus</i> Genus of viruses

Sobemovirus is a genus of non-enveloped, positive-strand RNA viruses which infect plants.. Plants serve as natural hosts. There are 21 species in this genus. Diseases associated with this genus include: mosaics and mottles.

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 wheat. However, eIF4G is exclusively found in domain Eukarya, and not in domains Bacteria or Archaea, which do not have capped mRNA. As such, eIF4G structure and function may vary between species, although the human EIF4G1 has been the focus of extensive studies.

Leaky scanning is a mechanism used during the initiation phase of eukaryotic translation that enables regulation of gene expression. During initiation, the small 40S ribosomal subunit "scans" or moves in a 5' --> 3' direction along the 5'UTR to locate a start codon to commence elongation. Sometimes, the scanning ribosome bypasses the initial AUG start codon and begins translation at further downstream AUG start codons. Translation in eukaryotic cells according to most scanning mechanisms occurs at the AUG start codon proximal to the 5' end of mRNA; however, the scanning ribosome may encounter an “unfavorable nucleotide context” around the start codon and continue scanning.

The Consensus Coding Sequence (CCDS) Project is a collaborative effort to maintain a dataset of protein-coding regions that are identically annotated on the human and mouse reference genome assemblies. The CCDS project tracks identical protein annotations on the reference mouse and human genomes with a stable identifier, and ensures that they are consistently represented by the National Center for Biotechnology Information (NCBI), Ensembl, and UCSC Genome Browser. The integrity of the CCDS dataset is maintained through stringent quality assurance testing and on-going manual curation.

<span class="mw-page-title-main">Translation regulation by 5′ transcript leader cis-elements</span>

Translation regulation by 5′ transcript leader cis-elements is a process in cellular translation.

References

  1. ↑ Edgil, D; Polacek, C; Harris, E (2006). "Dengue virus utilizes a novel strategy for translation initiation when cap-dependent translation is inhibited". Journal of Virology. 80 (6): 2976–86. doi:10.1128/JVI.80.6.2976-2986.2006. PMC   1395423 . PMID   16501107.
  2. ↑ Fütterer, Johannes; Kiss-László, Zsuzsanna; Hohn, Thomas (1993). "Nonlinear ribosome migration on cauliflower mosaic virus 35S RNA". Cell. 73 (4): 789–802. doi:10.1016/0092-8674(93)90257-Q. PMID   8500171.
  3. ↑ Dominguez, DI; Ryabova, LA; Pooggin, MM; Schmidt-Puchta, W; Fütterer, J; Hohn, T (1998). "Ribosome shunting in cauliflower mosaic virus. Identification of an essential and sufficient structural element". The Journal of Biological Chemistry. 273 (6): 3669–78. doi: 10.1074/jbc.273.6.3669 . PMID   9452497.
  4. ↑ Ryabova, Lyubov A.; Pooggin, Mikhail M.; Hohn, Thomas (2006). "Translation reinitiation and leaky scanning in plant viruses". Virus Research. 119 (1): 52–62. doi:10.1016/j.virusres.2005.10.017. PMID   16325949.
  5. ↑ Pooggin, MM; Fütterer, J; Skryabin, KG; Hohn, T (1999). "A short open reading frame terminating in front of a stable hairpin is the conserved feature in pregenomic RNA leaders of plant pararetroviruses". The Journal of General Virology. 80 (8): 2217–28. doi: 10.1099/0022-1317-80-8-2217 . PMID   10466822.
  6. ↑ Pooggin, MM; Hohn, T; Fütterer, J (2000). "Role of a short open reading frame in ribosome shunt on the cauliflower mosaic virus RNA leader". The Journal of Biological Chemistry. 275 (23): 17288–96. doi: 10.1074/jbc.M001143200 . PMID   10747993.
  7. ↑ Fütterer, J; Potrykus, I; Bao, Y; Li, L; Burns, TM; Hull, R; Hohn, T (1996). "Position-dependent ATT initiation during plant pararetrovirus rice tungro bacilliform virus translation". Journal of Virology. 70 (5): 2999–3010. PMC   190159 . PMID   8627776.
  8. ↑ Pooggin, M. M.; Ryabova, LA; He, X; Fütterer, J; Hohn, T (2006). "Mechanism of ribosome shunting in Rice tungro bacilliform pararetrovirus". RNA. 12 (5): 841–50. doi:10.1261/rna.2285806. PMC   1440904 . PMID   16556934.
  9. ↑ De Breyne, S; Simonet, V; Pelet, T; Curran, J (2003). "Identification of a cis-acting element required for shunt-mediated translational initiation of the Sendai virus Y proteins". Nucleic Acids Research. 31 (2): 608–18. doi:10.1093/nar/gkg143. PMC   140508 . PMID   12527769.
  10. ↑ Latorre, P; Kolakofsky, D; Curran, J (1998). "Sendai virus Y proteins are initiated by a ribosomal shunt". Molecular and Cellular Biology. 18 (9): 5021–31. doi:10.1128/mcb.18.9.5021. PMC   109087 . PMID   9710586.
  11. ↑ Yueh, A; Schneider, RJ (1996). "Selective translation initiation by ribosome jumping in adenovirus-infected and heat-shocked cells". Genes & Development. 10 (12): 1557–67. doi: 10.1101/gad.10.12.1557 . PMID   8666238.
  12. ↑ Xi, Quiaron (2005). "Regulation of Translation by Ribosome Shunting through Phosphotyrosine-Dependent Coupling of Adenovirus Protein 100k to Viral mRNAs". Journal of Virology. 14 (9): 5676–5683. PMC   1082770 .
  13. ↑ Yueh, A; Schneider, RJ (2000). "Translation by ribosome shunting on adenovirus and hsp70 mRNAs facilitated by complementarity to 18S rRNA". Genes & Development. 14 (4): 414–21. PMC   316380 . PMID   10691734.
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