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Biochemical Society Transactions Feb 2022Proteostasis refers to a delicately tuned balance between the processes of protein synthesis, folding, localization, and the degradation of proteins found inside and... (Review)
Review
Proteostasis refers to a delicately tuned balance between the processes of protein synthesis, folding, localization, and the degradation of proteins found inside and outside cells. Our understanding of extracellular proteostasis is rather limited and largely restricted to knowledge of 11 currently established extracellular chaperones (ECs). This review will briefly outline what is known of the established ECs, before moving on to discuss experimental strategies used to identify new members of this growing family, and an examination of a group of putative new ECs identified using one of these approaches. An observation that emerges from an analysis of the expanding number of ECs is that all of these proteins are multifunctional. Strikingly, the armory of activities each possess uniquely suit them as a group to act together at sites of tissue damage, infection, and inflammation to restore homeostasis. Lastly, we highlight outstanding questions to guide future research in this field.
Topics: Molecular Chaperones; Protein Biosynthesis; Protein Folding; Proteostasis
PubMed: 34940856
DOI: 10.1042/BST20210369 -
Trends in Biotechnology Jul 2020Proteins found in nature have traditionally been the most frequently used biocatalysts to produce numerous natural products ranging from commodity chemicals to... (Review)
Review
Proteins found in nature have traditionally been the most frequently used biocatalysts to produce numerous natural products ranging from commodity chemicals to pharmaceuticals. Protein engineering has emerged as a powerful biotechnological toolbox in the development of metabolic engineering, particularly for the biosynthesis of natural products. Recently, protein engineering has become a favored method to improve enzymatic activity, increase enzyme stability, and expand product spectra in natural product biosynthesis. This review summarizes recent advances and typical strategies in protein engineering, highlighting the paramount role of protein engineering in improving and diversifying the biosynthesis of natural products. Future prospects and research directions are also discussed.
Topics: Biological Products; Biotechnology; Humans; Metabolic Engineering; Protein Biosynthesis; Protein Engineering
PubMed: 31954530
DOI: 10.1016/j.tibtech.2019.12.008 -
Yi Chuan = Hereditas May 2020With the rapid development of high-throughput sequencing technology and translatome studies, the translational ability of circular RNA (circRNA) has gradually attracted... (Review)
Review
With the rapid development of high-throughput sequencing technology and translatome studies, the translational ability of circular RNA (circRNA) has gradually attracted much attention. Previous studies have shown that circRNA itself can be translated into proteins, whose function is closely related to the occurrence and development of human diseases. And it is expected to become an ideal substitute for mRNA, which can be widely used in protein engineering in the future. In this review, we systematically summarize the sources, biogenesis and features of circRNA, the driving models of circRNA translation, identification and functional verification of circRNA translation. We also sum up the latest research progress of circRNA translation in human diseases and its application in protein engineering, and make prospective anticipations for future research directions, which may offer more theoretical references for related researches in this field.
Topics: Humans; Protein Biosynthesis; RNA, Circular; RNA, Messenger
PubMed: 32431294
DOI: 10.16288/j.yczz.19-354 -
The Journal of Biological Chemistry Aug 2023The notion that errors in protein synthesis are universally harmful to the cell has been questioned by findings that suggest such mistakes may sometimes be beneficial....
The notion that errors in protein synthesis are universally harmful to the cell has been questioned by findings that suggest such mistakes may sometimes be beneficial. However, how often these beneficial mistakes arise from programmed changes in gene expression as opposed to reduced accuracy of the translation machinery is still unclear. A new study published in JBC shows that some bacteria have beneficially evolved the ability to mistranslate specific parts of the genetic code, a trait that allows improved antibiotic resistance.
Topics: Bacteria; Genetic Code; Protein Biosynthesis; RNA, Transfer
PubMed: 37380073
DOI: 10.1016/j.jbc.2023.104974 -
Biochemical Society Transactions Dec 2021Cellular ageing is one of the main drivers of organismal ageing and holds keys towards improving the longevity and quality of the extended life. Elucidating mechanisms... (Review)
Review
Cellular ageing is one of the main drivers of organismal ageing and holds keys towards improving the longevity and quality of the extended life. Elucidating mechanisms underlying the emergence of the aged cells as well as their altered responses to the environment will help understanding the evolutionarily defined longevity preferences across species with different strategies of survival. Much is understood about the role of alterations in the DNA, including many epigenetic modifications such as methylation, in relation to the aged cell phenotype. While transcriptomes of the aged cells are beginning to be better-characterised, their translational responses remain under active investigation. Many of the translationally controlled homeostatic pathways are centred around mitigation of DNA damage, cell stress response and regulation of the proliferative potential of the cells, and thus are critical for the aged cell function. Translation profiling-type studies have boosted the opportunities in discovering the function of protein biosynthesis control and are starting to be applied to the aged cells. Here, we provide a summary of the current knowledge about translational mechanisms considered to be commonly altered in the aged cells, including the integrated stress response-, mechanistic target of Rapamycin- and elongation factor 2 kinase-mediated pathways. We enlist and discuss findings of the recent works that use broad profiling-type approaches to investigate the age-related translational pathways. We outline the limitations of the methods and the remaining unknowns in the established ageing-associated translation mechanisms, and flag translational mechanisms with high prospective importance in ageing, for future studies.
Topics: Animals; Cellular Senescence; DNA Damage; Homeostasis; Humans; Protein Biosynthesis; Transcriptome
PubMed: 34913471
DOI: 10.1042/BST20210844 -
Molecular Psychiatry Aug 2022Transfer (t)RNAs are 70-90 nucleotide small RNAs highly regulated by 43 different types of epitranscriptomic modifications and requiring aminoacylation ('charging') for... (Review)
Review
Transfer (t)RNAs are 70-90 nucleotide small RNAs highly regulated by 43 different types of epitranscriptomic modifications and requiring aminoacylation ('charging') for mRNA decoding and protein synthesis. Smaller cleavage products of mature tRNAs, or tRNA fragments, have been linked to a broad variety of noncanonical functions, including translational inhibition and modulation of the immune response. Traditionally, knowledge about tRNA regulation in brain is derived from phenotypic exploration of monogenic neurodevelopmental and neurodegenerative diseases associated with rare mutations in tRNA modification genes. More recent studies point to the previously unrecognized potential of the tRNA regulome to affect memory, synaptic plasticity, and affective states. For example, in mature cortical neurons, cytosine methylation sensitivity of the glycine tRNA family (tRNA) is coupled to glycine biosynthesis and codon-specific alterations in ribosomal translation together with robust changes in cognition and depression-related behaviors. In this Review, we will discuss the emerging knowledge of the neuronal tRNA landscape, with a focus on epitranscriptomic tRNA modifications and downstream molecular pathways affected by alterations in tRNA expression, charging levels, and cleavage while mechanistically linking these pathways to neuropsychiatric disease and provide insight into future areas of study for this field.
Topics: Protein Biosynthesis; RNA, Transfer; Codon; RNA, Messenger; Glycine
PubMed: 35505091
DOI: 10.1038/s41380-022-01585-9 -
IEEE/ACM Transactions on Computational... 2023We derive a deterministic mathematical model for the flow of ribosomes along a mRNA called the ribosome flow model with extended objects and abortions (RFMEOA). This...
We derive a deterministic mathematical model for the flow of ribosomes along a mRNA called the ribosome flow model with extended objects and abortions (RFMEOA). This model incorporates important cellular features such as every ribosome covers several codons and they may detach from various regions along the track due to more realistic biological situations including phenomena of ribosome-ribosome collisions. We prove that the ribosome density profile along the mRNA in the RFMEOA and in particular, the protein production rate converge to a unique steady-state. Simulations of the RFMEOA demonstrate a surprising result that an increase in the initiation rate may sometimes lead to a decrease in the production rate. We believe that this model could be helpful to provide insight into the effects of premature termination on the protein expression and be useful for understanding and re-engineering the translation process.
Topics: Ribosomes; Protein Biosynthesis; RNA, Messenger; Codon; Models, Biological
PubMed: 36044491
DOI: 10.1109/TCBB.2022.3203171 -
Signal Transduction and Targeted Therapy Feb 2024Protein translation is a tightly regulated cellular process that is essential for gene expression and protein synthesis. The deregulation of this process is increasingly... (Review)
Review
Protein translation is a tightly regulated cellular process that is essential for gene expression and protein synthesis. The deregulation of this process is increasingly recognized as a critical factor in the pathogenesis of various human diseases. In this review, we discuss how deregulated translation can lead to aberrant protein synthesis, altered cellular functions, and disease progression. We explore the key mechanisms contributing to the deregulation of protein translation, including functional alterations in translation factors, tRNA, mRNA, and ribosome function. Deregulated translation leads to abnormal protein expression, disrupted cellular signaling, and perturbed cellular functions- all of which contribute to disease pathogenesis. The development of ribosome profiling techniques along with mass spectrometry-based proteomics, mRNA sequencing and single-cell approaches have opened new avenues for detecting diseases related to translation errors. Importantly, we highlight recent advances in therapies targeting translation-related disorders and their potential applications in neurodegenerative diseases, cancer, infectious diseases, and cardiovascular diseases. Moreover, the growing interest lies in targeted therapies aimed at restoring precise control over translation in diseased cells is discussed. In conclusion, this comprehensive review underscores the critical role of protein translation in disease and its potential as a therapeutic target. Advancements in understanding the molecular mechanisms of protein translation deregulation, coupled with the development of targeted therapies, offer promising avenues for improving disease outcomes in various human diseases. Additionally, it will unlock doors to the possibility of precision medicine by offering personalized therapies and a deeper understanding of the molecular underpinnings of diseases in the future.
Topics: Humans; Ribosomes; Neoplasms; RNA, Messenger; Protein Biosynthesis; Biological Phenomena
PubMed: 38388452
DOI: 10.1038/s41392-024-01749-9 -
The Journal of Biological Chemistry Jul 2020Bacteria must rapidly respond to both intracellular and environmental changes to survive. One critical mechanism to rapidly detect and adapt to changes in environmental... (Review)
Review
Bacteria must rapidly respond to both intracellular and environmental changes to survive. One critical mechanism to rapidly detect and adapt to changes in environmental conditions is control of gene expression at the level of protein synthesis. At each of the three major steps of translation-initiation, elongation, and termination-cells use stimuli to tune translation rate and cellular protein concentrations. For example, changes in nutrient concentrations in the cell can lead to translational responses involving mechanisms such as dynamic folding of riboswitches during translation initiation or the synthesis of alarmones, which drastically alter cell physiology. Moreover, the cell can fine-tune the levels of specific protein products using programmed ribosome pausing or inducing frameshifting. Recent studies have improved understanding and revealed greater complexity regarding long-standing paradigms describing key regulatory steps of translation such as start-site selection and the coupling of transcription and translation. In this review, we describe how bacteria regulate their gene expression at the three translational steps and discuss how translation is used to detect and respond to changes in the cellular environment. Finally, we appraise the costs and benefits of regulation at the translational level in bacteria.
Topics: Adaptation, Physiological; Bacteria; Bacterial Proteins; Protein Biosynthesis
PubMed: 32518156
DOI: 10.1074/jbc.REV120.012742 -
ELife Feb 2024A new in vitro system called Rec-Seq sheds light on how mRNA molecules compete for the machinery that translates their genetic sequence into proteins.
A new in vitro system called Rec-Seq sheds light on how mRNA molecules compete for the machinery that translates their genetic sequence into proteins.
Topics: Protein Biosynthesis; Ribosomes; RNA, Messenger
PubMed: 38393777
DOI: 10.7554/eLife.96304