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Mechanisms of Translational Control: From Eukaryotic Ribosome Scanning to Reinitiation – Cell Biology

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class="content-area" id="primary"> <main class="site-main" id="main"> <article id="post-86" class="post-86 post type-post status-publish format-standard has-post-thumbnail hentry category-eukaryotic-ribosome-scanning tag-eukaryotic-translation tag-protein-synthesis-regulation tag-reinitiation tag-ribosome-scanning tag-rna-binding-proteins tag-translational-control tag-upstream-open-reading-frames-uorfs tag-viral-translation" itemtype="https://schema.org/CreativeWork" itemscope> <div class="inside-article"> <div class="featured-image page-header-image-single "> <img width="1200" height="628" src="https://cellbiology.blog/archive/wp-content/uploads/2024/11/banner-32-min-scaled-e1731591657534.jpg" class="attachment-full size-full" alt="" itemprop="image" decoding="async" fetchpriority="high" /> </div> <header class="entry-header"> <h1 class="entry-title" itemprop="headline">Mechanisms of Translational Control: From Eukaryotic Ribosome Scanning to Reinitiation</h1> <div class="entry-meta"> <span class="posted-on"><time class="entry-date published" datetime="2024-11-14T19:08:47+05:30" itemprop="datePublished">November 14, 2024</time></span> <span class="byline">by <span class="author vcard" itemprop="author" itemtype="https://schema.org/Person" itemscope><a class="url fn n" href="https://cellbiology.blog/archive/author/cellbiology/" title="View all posts by cellbiology" rel="author" itemprop="url"><span class="author-name" itemprop="name">cellbiology</span></a></span></span> </div> </header> <div class="entry-content" itemprop="text"> <h4><b>Introduction</b></h4> <p><span style="font-weight: 400;">This functional regulation positions translational control as a controller of gene expression since it encourages strategies for how genetic information is translated into functional proteins.</span><span style="font-weight: 400;"> Similar to transcriptional regulation, while transcriptional regulation controls the synthesis of mRNAs, translational regulation regulates the use of the mRNAs present and hence controls protein levels without changing the mRNA levels. This regulation is critical for cellular actions/reactions to stimuli, stress conditions, and developmental process control. The controls in eukaryotic cells are more complicated since they comprise interactions between mRNA, ribosomes, and other regulatory proteins. Probably the most well-known process is ribosome scanning, which aims at finding the best-fit start codon for translating the mRNA. However, translational control goes beyond scanning and regulation and includes reinitiation and regulation by upstream open reading frames (uORFs). Knowledge of these mechanisms is valuable for the development of theories related to cell regulation, mechanisms of viral diseases, and treatment of different diseases.</span></p> <h4><b>Eukaryotic Ribosome Scanning: The Basics</b></h4> <p><span style="font-weight: 400;">Translation initiation in eukaryotic cells takes place through ribosome scanning, in which the small 40S ribosomal subunit, coupled with the initiation factors, initially binds to the 5 ‘ cap structure in the mRNA and moves through the 5 ‘ UTR to find out the start codon AUG. This scanning model makes certain that the ribosome comes to the right start site to synthesize the correct protein. The efficiency of scanning is affected by the sequence that is in context with the start codon, usually referred to as the Kozak sequence. Initiation is most efficient when the AUG codon is followed by a preferred sequence and concluded by the preferred downstream sequence, which many researchers indicate as GCCA/GCCAUGG.</span></p> <h4><b>Translational Barriers: Secondary Structures and uORFs</b></h4> <p><span style="font-weight: 400;">However, scanning is not a smooth process in the following sense. The upstream open reading frame (uORF) is often located in the 5’ untranslated region (5’ UTRs) of a gene, and it is forecasted that many eukaryotic mRNAs contain complex secondary structures as well as hairpins and stem-loops that can hinder the 5’ scanning ribosome. For example, mRNA structures with thermodynamically favorable conformations can become hurdles, leading to ribosomal pauses or delayed scanning. When the structures under consideration are rather less stable, the ribosomes, with all their might, help translation go on, whereas the highly stable formations hinder translation rather than resistance to more stable structures like those with very low free energy changes (ΔG = -50 kcal/mol), for instance, presents rather great barriers.</span></p> <p><span style="font-weight: 400;">In addition, upstream open reading frames (uORFs) located in the 5’UTR can control translation depending on their position for the provision of other start sites. Since the translation of a uORF can remove ribosomes from the mRNA before the main coding sequence is reached, it can decrease protein productivity. These specific residues are the positioning and sequence context. of these uORFs responsible for influencing the ribosome either to re-initiate translation at the downstream start codon or to disengage.</span></p> <p></div></div> <div style="background: #f7f7f7;border: 1px solid rgba(0, 0, 0, 0.07);"> <div style="padding: 30px;"><div class="Adblock-main"> <div class="Adblock-head"> <h2>Yearwise Publication Trend on <b>“<a href="https://cellbiology.blog/publication-trends/index/eukaryotic ribosome scanning" target="_blank" title="eukaryotic ribosome scanning - yearwise publication trends">eukaryotic ribosome scanning</a>”</b></h2> </div> </div><div class="results-container"><div class="chart-block" style="padding:15px;"> <div class="left"> <div id="results" class="results"></div> </div> <div class="right"> <div class="chart-container"><canvas id="publicationChart"></canvas></div> </div> <div class="keywordsdiv"> <div style="text-align:center;"><b>Find publication trends on relevant topics</b> </div> <span class="gp-icon icon-tags"><svg viewBox="0 0 512 512" aria-hidden="true" xmlns="http://www.w3.org/2000/svg" width="1em" height="1em"><path d="M20 39.5c-8.836 0-16 7.163-16 16v176c0 4.243 1.686 8.313 4.687 11.314l224 224c6.248 6.248 16.378 6.248 22.626 0l176-176c6.244-6.244 6.25-16.364.013-22.615l-223.5-224A15.999 15.999 0 00196.5 39.5H20zm56 96c0-13.255 10.745-24 24-24s24 10.745 24 24-10.745 24-24 24-24-10.745-24-24z"></path><path d="M259.515 43.015c4.686-4.687 12.284-4.687 16.97 0l228 228c4.686 4.686 4.686 12.284 0 16.97l-180 180c-4.686 4.687-12.284 4.687-16.97 0-4.686-4.686-4.686-12.284 0-16.97L479.029 279.5 259.515 59.985c-4.686-4.686-4.686-12.284 0-16.97z"></path></svg></span> <span id="keyword-stats"></span> </div> </div></div></div><div class="inside-article"><style> table { margin: 0 0 1.5em; 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if (!statistics || Object.keys(statistics).length === 0) { resultsContainer.innerHTML = '<p>No data found.</p>'; return; } var tableHTML = `<div class='pub-scroll'> <table class='tablediv' border='1' cellspacing='0' cellpadding='0'> <tr> <th>Year</th> <th>Publication Count</th> </tr>`; Object.entries(statistics).sort(([yearA], [yearB]) => yearB - yearA).forEach(([year, count]) => { const displayCount = count === 0 ? 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This mechanism is common in mRNAs having short uORFs, from where ribosomes that terminate near the start of the main coding sequence still have some initiation factors for reinitiating U/A again. Several factors were identified to regulate the reinitiation efficiency, including the distance between the uORF stop codon and the downstream AUG, sequence element, and structure of the ribosomal.</span></p> <p><span style="font-weight: 400;">Coveted in the assembly of viral genomes, reinitiation has a crucial role in synthesizing various proteins from a single mRNA strand. For example, where reinitiation events can change the infection rate of the cauliflower mosaic virus depending on the mutation of the translation sites for initiation, control of reinitiation sites dictates the viral replication and protein synthesis. Multiple initiation and termination codons can be present in close range, and the ribosomes therefore run multiple initiation and termination sequences in turn, thus raising the coding number for each mRNA.</span></p> <h4><b>Impact of Upstream AUGs and Non-Canonical Initiation Sites</b></h4> <p><span style="font-weight: 400;">It is also noteworthy that there are upstream AUG codons and non-canonical initiation sites to complicate the regulation of translation. Sometimes other AUG triplets that are present upstream of the primary start are masks used to control the availability of the main code sequence. These upstream sites may be targeted by ribosomes to generate alternative protein isoforms or truncated proteins that have different or are regulatory.</span></p> <p><span style="font-weight: 400;">For instance, Schlossmann’s et al. work has indicated that the dictionary genetics, etc., and genomics The effectiveness of this shunting is determined by the context within which the upstream AUGs are located and the architecture of the 5’ UTR. This mechanism is particularly important during stress, when signaling pathways in a cell may alter the availability of initiation factors, leading to a regulation of translation from specific IRES sites.</span></p> <h4><b>Reinitiation in Viral Translation: Exploiting Host Machinery</b></h4> <p><span style="font-weight: 400;">Some viruses use the host cell’s translational machinery to its optimum to synthesize viral proteins, more of which are involved in leaky scanning and reinitiation. For example, the FMDV has two distinct initiation sites, due to which it synthesizes different protein isoforms that are necessary for its replication cycle. Access to these sites is differentially controlled by other nucleotide sequences that affect the binding of the ribosome and the relative concentration of the formed protein.</span></p> <p><span style="font-weight: 400;">Furthermore, multiple genes can be coded in viral mRNA, as the genome of many of the known viruses consists of a single strand that may have more than one reading frame. This bicistronic organization could be problematic for the host translation machinery because the ribosome has to traverse through complicated mRNA structures and perform selective reinitiation steps to synthesize the required components of the virus. Such viral strategies revealed important information about potential antiviral sites that could prevent reinitiation or decrease the divergence in a ribosome scanning fidelity.</span></p> <p></div></div> <div style="background: #f7f7f7;border: 1px solid rgba(0, 0, 0, 0.07);"> <div style="padding: 30px;"><div class="Adblock-main"> <div class="Adblock-head"> <h2>Recent Publications on <b>“<a href="https://cellbiology.blog/recent-publications/index/eukaryotic ribosome scanning" target="_blank" rel="noopener" title="eukaryotic ribosome scanning - yearwise publication list">eukaryotic ribosome scanning</a>”</b></h2> </div> </div> <div class="pb-main"><div class="article-scroll"><div id="results_recent" class="results"></div></div><div class="keywordsdiv" style="margin: 0px 15px;margin-top:20px;"> <div style="text-align:center;"><b>Find publications on relevant topics</b> </div> <span class="gp-icon icon-tags"><svg viewBox="0 0 512 512" aria-hidden="true" xmlns="http://www.w3.org/2000/svg" width="1em" height="1em"><path d="M20 39.5c-8.836 0-16 7.163-16 16v176c0 4.243 1.686 8.313 4.687 11.314l224 224c6.248 6.248 16.378 6.248 22.626 0l176-176c6.244-6.244 6.25-16.364.013-22.615l-223.5-224A15.999 15.999 0 00196.5 39.5H20zm56 96c0-13.255 10.745-24 24-24s24 10.745 24 24-10.745 24-24 24-24-10.745-24-24z"></path><path d="M259.515 43.015c4.686-4.687 12.284-4.687 16.97 0l228 228c4.686 4.686 4.686 12.284 0 16.97l-180 180c-4.686 4.687-12.284 4.687-16.97 0-4.686-4.686-4.686-12.284 0-16.97L479.029 279.5 259.515 59.985c-4.686-4.686-4.686-12.284 0-16.97z"></path></svg></span> <span id="keyword-papers"></span> </div></div></div><div class="inside-article"> <style> .pb-main{ border: solid 1px #ccc; 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publicationBlock.innerHTML = publicationHTML; resultsContainer.appendChild(publicationBlock); }); } function displayKeywordPapers(keywords) { var resultsContainer = document.getElementById('keyword-papers'); resultsContainer.innerHTML = ''; if (!keywords || keywords.length === 0) { resultsContainer.innerHTML = '<p>No data found.</p>'; return; } var keywordHTML = ''; keywords.forEach((key, index) => { let key_replace = key.replace(/ /g, '-'); key_replace = key_replace.toLowerCase(); keywordHTML += `<a href="https://cellbiology.blog/recent-publications/index/${key_replace}" target="_blank" title="${key} - publication list">${key}</a>`; if (index < keywords.length - 1) { keywordHTML += ', '; } }); resultsContainer.innerHTML = keywordHTML; } // Call the function with the PHP data var recent_papers = [ { "title": "Host-like RNA Elements Regulate Virus Translation.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/38543832", "publishedDate": "2024" }, { "title": "Yeast eIF2A has a minimal role in translation initiation and uORF-mediated translational control in vivo.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/38266075", "publishedDate": "2024" }, { "title": "Leaky ribosomal scanning enables tunable translation of bicistronic ORFs in green algae.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/39091764", "publishedDate": "2024" }, { "title": "Critical -parameters influence STructure assisted RNA translation (START) initiation on non-AUG codons in eukaryotes.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/38863530", "publishedDate": "2024" }, { "title": "A second-generation eIF4A RNA helicase inhibitor exploits translational reprogramming as a vulnerability in triple-negative breast cancer.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/38232291", "publishedDate": "2024" }, { "title": "Deciphering the regulatory landscape of natural yeast Transcript Leaders.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/39005336", "publishedDate": "2024" }, { "title": "Structural basis for translational control by the human 48S initiation complex.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/39289545", "publishedDate": "2024" }, { "title": "The Roles of eIF4G2 in Leaky Scanning and Reinitiation on the Human Dual-Coding POLG mRNA.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/38138978", "publishedDate": "2023" }, { "title": "The molecular basis of translation initiation and its regulation in eukaryotes.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/38052923", "publishedDate": "2023" }, { "title": "Exploring the Targeting Spectrum of Rocaglates Among eIF4A Homologs.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/36882295", "publishedDate": "2023" }, { "title": "Yeast eIF2A has a minimal role in translation initiation and uORF-mediated translational control in vivo.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/37986989", "publishedDate": "2023" }, { "title": "PRRC2 proteins impact translation initiation by promoting leaky scanning.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/36869665", "publishedDate": "2023" }, { "title": "DAP5 Binding to the FGF-9 mRNA 5\\\\\\' UTR is Structurally-Dependent.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/35554027", "publishedDate": "2022" }, { "title": "Specific Mechanisms of Translation Initiation in Higher Eukaryotes: The eIF4G2 Story.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/36517212", "publishedDate": "2022" }, { "title": "Distance-dependent inhibition of translation initiation by downstream out-of-frame AUGs is consistent with a Brownian ratchet process of ribosome scanning.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/36510274", "publishedDate": "2022" }, { "title": "Stepwise assembly of the eukaryotic translation initiation factor 2 complex.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/35031321", "publishedDate": "2022" }, { "title": "Zotatifin, an eIF4A-Selective Inhibitor, Blocks Tumor Growth in Receptor Tyrosine Kinase Driven Tumors.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/34900714", "publishedDate": "2021" }, { "title": "Dynamic eIF3a O-GlcNAcylation controls translation reinitiation during nutrient stress.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/34887587", "publishedDate": "2021" }, { "title": "Bi-directional ribosome scanning controls the stringency of start codon selection.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/34782646", "publishedDate": "2021" }, { "title": "1-Aminomethyl SAR in a novel series of flavagline-inspired eIF4A inhibitors: Effects of amine substitution on cell potency and in vitro PK properties.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/34353608", "publishedDate": "2021" } ]; var keywordsArray = ["Translational control","ribosome scanning","reinitiation","upstream open reading frames (uORFs)","eukaryotic translation","RNA-binding proteins","viral translation","protein synthesis regulation"]; displayResults_recent(recent_papers); displayKeywordPapers(keywordsArray); // function stripslashes(str) { // if (typeof str === 'string') { // return str.replace(/\/g, ''); // } // } </script></p> <h4><b>Translational Regulation by RNA-Binding Proteins and Initiation Factors</b></h4> <p><span style="font-weight: 400;">Therefore, the process of translational control is equally regulated by RNA-binding proteins and the initiation factors that bind to concrete sequences or motifs within the mRNA. Most of these proteins can either facilitate or modulate the ribosome binding process, affect scanner speed, or facilitate reinitiation. For example, for the recruitment of initiation factors such as eIF4G and eIF4A, it is essential for the melting secondary structures that the progress of the ribosome is hindered by. Regulatory proteins immobilized initiation factors, thus commanding translation factors into unique mRNAs during stress or development changes.</span></p> <p><span style="font-weight: 400;">This, coupled with the fact that ribosomes, initiation factors, and RNA-binding proteins form a multifaceted interacting system, will offer an opportunity to constantly regulate translation rates to the requirements of the cell. Such fine-tuning is often required in stress responses where it is critical to drastically change the synthesis rates of certain proteins to counteract cell damage and re-establish normal functioning.</span></p> <h4><b>Applications and Therapeutic Implications</b></h4> <p><span style="font-weight: 400;">Knowledge of the different strategies of translational control provides hope for intervention in diseases associated with aberrant protein synthesis. Strategies that focus on certain steps in ribosome scanning or reinitiation can reveal how protein levels can be up or down-regulated in cancer, viral infections, and genetic disorders. For instance, regulating uORFs or preventing unauthorized reinitiation could return ‘normal’ to the translation machinery of oncogene-altered or virus-co-opted cells.</span></p> <p><span style="font-weight: 400;">However, selective inhibition of certain initiation factors or selective alteration of the scanning behavior of the ribosome could open up possibilities of a selective translation ‘remodeling’ that would allow accurate control of protein synthesis without necessary changes at the level of transcription. This is an approach of great promise for diseases that rest on protein misfolding, aggregation, or overexpression—the neurodegenerative states primarily included.</span></p> <h4><b>Conclusion</b></h4> <p><span style="font-weight: 400;">Global regulation in eukaryotic cells involves a multitude of methods, including ribosome scanning and reinitiation and uORFs and RBPs. These processes make it possible for the cell to very quickly change its rate of protein synthesis due to the internal and external changes so that the cell remains functional and in homeostasis. Further investigation into these regulatory mechanisms will provide new targets for the development of treatments as well as ways to modulate translation for the treatment of a multitude of diseases. The unrelenting dissection of translational control remains a source of understanding the dynamics of protein synthesis and its relationship to essential life processes as well as human diseases.</span></p> <p></p> <h4><b>References</b></h4> <ol> <li>Kozak, M., 1986. <a href="https://www.pnas.org/doi/abs/10.1073/pnas.83.9.2850">Influences of mRNA secondary structure on initiation by eukaryotic ribosomes.</a> <i>Proceedings of the National Academy of Sciences</i>, <i>83</i>(9), pp.2850-2854.</li> <li>Clarke, B.E., Sangar, D.V., Burroughs, J.N., Newton, S.E., Carroll, A.R. and Rowlands, D.J., 1985. <a href="https://www.microbiologyresearch.org/content/journal/jgv/10.1099/0022-1317-66-12-2615">Two initiation sites for foot-and-mouth disease virus polyprotein in vivo.</a> <i>Journal of General Virology</i>, <i>66</i>(12), pp.2615-2626.</li> <li>Sarkar, G., Pelletier, J., Bassel-Duby, R., Jayasuriya, A., Fields, B.N. and Sonenberg, N., 1985. <a href="https://journals.asm.org/doi/abs/10.1128/jvi.54.3.720-725.1985">Identification of a new polypeptide coded by reovirus gene S1.</a> <i>Journal of virology</i>, <i>54</i>(3), pp.720-725.</li> <li>Persing, D.H., Varmus, H.E. and Ganem, D., 1985. <a href="https://www.pnas.org/doi/abs/10.1073/pnas.82.10.3440">A frameshift mutation in the pre-S region of the human hepatitis B virus genome allows production of surface antigen particles but eliminates binding to polymerized albumin.</a> <i>Proceedings of the National Academy of Sciences</i>, <i>82</i>(10), pp.3440-3444.</li> <li>Kozak, M., 1984. <a href="https://academic.oup.com/nar/article/12/9/3873/1055656#google_vignette">Selection of initiation sites by eucaryotic ribosomes: effect of inserting AUG triplets upstream from the coding sequence for preproinsulin.</a> <i>Nucleic acids research</i>, <i>12</i>(9), pp.3873-3893.</li> <li>Dixon, L.K. and Hohn, T., 1984. <a href="https://www.embopress.org/doi/abs/10.1002/j.1460-2075.1984.tb02203.x">Initiation of translation of the cauliflower mosaic virus genome from a polycistronic mRNA: evidence from deletion mutagenesis.</a> <i>The EMBO Journal</i>, <i>3</i>(12), pp.2731-2736.</li> <li>Bellini, W.J., Englund, G., Rozenblatt, S., Arnheiter, H. and Richardson, C.D., 1985. <a href="https://journals.asm.org/doi/abs/10.1128/jvi.53.3.908-919.1985">Measles virus P gene codes for two proteins.</a> <i>Journal of virology</i>, <i>53</i>(3), pp.908-919.</li> </ol> <p></div></div> <div style="background: #f7f7f7;border: 1px solid rgba(0, 0, 0, 0.07);"> <div style="padding: 30px;"><div class="Adblock-main"> <div class="Adblock-head"> <h2>Top Experts on “<b style="color:#000;font-size:22px;">eukaryotic ribosome scanning</b>“</h2> </div> </div><div class="author-main"><div id="results_author"></div><div style="text-align: center;"><a class="register-button" href="https://cellbiology.blog/expert-search" 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