-
Biomedicine & Pharmacotherapy =... Jun 2024The endoplasmic reticulum (ER) is important to cells because of its essential functions, including synthesizing three major nutrients and ion transport. When cellular... (Review)
Review
The endoplasmic reticulum (ER) is important to cells because of its essential functions, including synthesizing three major nutrients and ion transport. When cellular homeostasis is disrupted, ER quality control (ERQC) system is activated effectively to remove misfolded and unfolded proteins through ER-phagy, ER-related degradation (ERAD), and molecular chaperones. When unfolded protein response (UPR) and ER stress are activated, the cell may be suffering a huge blow, and the most probable consequence is apoptosis. The membrane contact points between the ER and sub-organelles contribute to communication between the organelles. The decrease in oxygen concentration affects the morphology and structure of the ER, thereby affecting its function and further disrupting the stable state of cells, leading to the occurrence of disease. In this study, we describe the functions of ER-, ERQC-, and ER-related membrane contact points and their changes under hypoxia, which will help us further understand ER and treat ER-related diseases.
Topics: Endoplasmic Reticulum; Humans; Animals; Endoplasmic Reticulum Stress; Unfolded Protein Response; Hypoxia; Apoptosis; Cell Hypoxia; Endoplasmic Reticulum-Associated Degradation
PubMed: 38781866
DOI: 10.1016/j.biopha.2024.116812 -
Molecular Cell Feb 2024Nearly 7 decades have elapsed since Francis Crick introduced the central dogma of molecular biology, as part of his ideas on protein synthesis, setting the fundamental... (Review)
Review
Nearly 7 decades have elapsed since Francis Crick introduced the central dogma of molecular biology, as part of his ideas on protein synthesis, setting the fundamental rules of sequence information transfer from DNA to RNAs and proteins. We have since learned that gene expression is finely tuned in time and space, due to the activities of RNAs and proteins on regulatory DNA elements, and through cell-type-specific three-dimensional conformations of the genome. Here, we review major advances in genome biology and discuss a set of ideas on gene regulation and highlight how various biomolecular assemblies lead to the formation of structural and regulatory features within the nucleus, with roles in transcriptional control. We conclude by suggesting further developments that will help capture the complex, dynamic, and often spatially restricted events that govern gene expression in mammalian cells.
Topics: Animals; Gene Expression Regulation; Genome; Protein Biosynthesis; Epigenesis, Genetic; DNA; Mammals
PubMed: 38242127
DOI: 10.1016/j.molcel.2023.12.032 -
Journal of Genetics and Genomics = Yi... Apr 2024Messenger RNA (mRNA) translation consists of initiation, elongation, termination, and ribosome recycling, carried out by the translation machinery, primarily including... (Review)
Review
Messenger RNA (mRNA) translation consists of initiation, elongation, termination, and ribosome recycling, carried out by the translation machinery, primarily including tRNAs, ribosomes, and translation factors (TrFs). Translational regulators transduce signals of growth and development, as well as biotic and abiotic stresses, to the translation machinery, where global or selective translational control occurs to modulate mRNA translation efficiency (TrE). As the basis of translational control, the translation machinery directly determines the quality and quantity of newly synthesized peptides and, ultimately, the cellular adaption. Thus, regulating the availability of diverse machinery components is reviewed as the central strategy of translational control. We provide classical signaling pathways (e.g., integrated stress responses) and cellular behaviors (e.g., liquid-liquid phase separation) to exemplify this strategy within different physiological contexts, particularly during host-microbe interactions. With new technologies developed, further understanding this strategy will speed up translational medicine and translational agriculture.
Topics: Ribosomes; Proteins; RNA, Messenger; Peptides; Gene Expression Regulation; Protein Biosynthesis
PubMed: 37536497
DOI: 10.1016/j.jgg.2023.07.009 -
Nucleic Acids Research Dec 2023Translation is critical for development as transcription in the oocyte and early embryo is silenced. To illustrate the translational changes during meiosis and...
Translation is critical for development as transcription in the oocyte and early embryo is silenced. To illustrate the translational changes during meiosis and consecutive two mitoses of the oocyte and early embryo, we performed a genome-wide translatome analysis. Acquired data showed significant and uniform activation of key translational initiation and elongation axes specific to M-phases. Although global protein synthesis decreases in M-phases, translation initiation and elongation activity increases in a uniformly fluctuating manner, leading to qualitative changes in translation regulation via the mTOR1/4F/eEF2 axis. Overall, we have uncovered a highly dynamic and oscillatory pattern of translational reprogramming that contributes to the translational regulation of specific mRNAs with different modes of polysomal occupancy/translation that are important for oocyte and embryo developmental competence. Our results provide new insights into the regulation of gene expression during oocyte meiosis as well as the first two embryonic mitoses and show how temporal translation can be optimized. This study is the first step towards a comprehensive analysis of the molecular mechanisms that not only control translation during early development, but also regulate translation-related networks employed in the oocyte-to-embryo transition and embryonic genome activation.
Topics: Embryonic Development; Gene Expression Regulation, Developmental; Meiosis; Oocytes; Protein Biosynthesis; RNA, Messenger; Animals; Mice
PubMed: 37950888
DOI: 10.1093/nar/gkad996 -
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 -
Cell Communication and Signaling : CCS Feb 2024The phenomenon of phase separation is quite common in cells, and it is involved in multiple processes of life activities. However, the current research on the... (Review)
Review
The phenomenon of phase separation is quite common in cells, and it is involved in multiple processes of life activities. However, the current research on the correlation between protein modifications and phase separation and the interference with the tendency of phase separation has some limitations. Here we focus on several post-translational modifications of proteins, including protein phosphorylation modification at multiple sites, methylation modification, acetylation modification, ubiquitination modification, SUMOylation modification, etc., which regulate the formation of phase separation and the stability of phase separation structure through multivalent interactions. This regulatory role is closely related to the development of neurodegenerative diseases, tumors, viral infections, and other diseases, and also plays essential functions in environmental stress, DNA damage repair, transcriptional regulation, signal transduction, and cell homeostasis of living organisms, which provides an idea to explore the interaction between novel protein post-translational modifications and phase separation. Video Abstract.
Topics: Phase Separation; Protein Processing, Post-Translational; Ubiquitination; Phosphorylation; Proteins; Acetylation
PubMed: 38347544
DOI: 10.1186/s12964-023-01380-1 -
The Biochemical Journal Aug 2023Post-translational modifications (PTMs) provide a rapid response to stimuli, finely tuning metabolism and gene expression and maintain homeostasis. Advances in mass... (Review)
Review
Post-translational modifications (PTMs) provide a rapid response to stimuli, finely tuning metabolism and gene expression and maintain homeostasis. Advances in mass spectrometry over the past two decades have significantly expanded the list of known PTMs in biology and as instrumentation continues to improve, this list will surely grow. While many PTMs have been studied in detail (e.g. phosphorylation, acetylation), the vast majority lack defined mechanisms for their regulation and impact on cell fate. In this review, we will highlight the field of PTM research as it currently stands, discussing the mechanisms that dictate site specificity, analytical methods for their detection and study, and the chemical tools that can be leveraged to define PTM regulation. In addition, we will highlight the approaches needed to discover and validate novel PTMs. Lastly, this review will provide a starting point for those interested in PTM biology, providing a comprehensive list of PTMs and what is known regarding their regulation and metabolic origins.
Topics: Humans; Protein Processing, Post-Translational; Phosphorylation; Acetylation; Cell Differentiation; Homeostasis
PubMed: 37610048
DOI: 10.1042/BCJ20220251 -
The Journal of Biological Chemistry Apr 2024The integrated stress response (ISR) refers to signaling pathways initiated by stress-activated eIF2α kinases. Distinct eIF2α kinases respond to different stress... (Review)
Review
The integrated stress response (ISR) refers to signaling pathways initiated by stress-activated eIF2α kinases. Distinct eIF2α kinases respond to different stress signals, including amino acid deprivation and mitochondrial stress. Such stress-induced eIF2α phosphorylation attenuates general mRNA translation and, at the same time, stimulates the preferential translation of specific downstream factors to orchestrate an adaptive gene expression program. In recent years, there have been significant new advances in our understanding of ISR during metabolic stress adaptation. Here, I discuss those advances, reviewing among others the ISR activation mechanisms in response to amino acid deprivation and mitochondrial stress. In addition, I review how ISR regulates the amino acid metabolic pathways and how changes in the ISR impact the physiology and pathology of various disease models.
Topics: Animals; Humans; Adaptation, Physiological; Amino Acids; eIF-2 Kinase; Eukaryotic Initiation Factor-2; Mitochondria; Phosphorylation; Protein Biosynthesis; Signal Transduction; Stress, Physiological
PubMed: 38462161
DOI: 10.1016/j.jbc.2024.107151 -
Proceedings of the National Academy of... Mar 2024The use of lipid nanoparticles (LNP) to encapsulate and deliver mRNA has become an important therapeutic advance. In addition to vaccines, LNP-mRNA can be used in many...
The use of lipid nanoparticles (LNP) to encapsulate and deliver mRNA has become an important therapeutic advance. In addition to vaccines, LNP-mRNA can be used in many other applications. For example, targeting the LNP with anti-CD5 antibodies (CD5/tLNP) can allow for efficient delivery of mRNA payloads to T cells to express protein. As the percentage of protein expressing T cells induced by an intravenous injection of CD5/tLNP is relatively low (4-20%), our goal was to find ways to increase mRNA-induced translation efficiency. We showed that T cell activation using an anti-CD3 antibody improved protein expression after CD5/tLNP transfection in vitro but not in vivo. T cell health and activation can be increased with cytokines, therefore, using mCherry mRNA as a reporter, we found that culturing either mouse or human T cells with the cytokine IL7 significantly improved protein expression of delivered mRNA in both CD4 and CD8 T cells in vitro. By pre-treating mice with systemic IL7 followed by tLNP administration, we observed significantly increased mCherry protein expression by T cells in vivo. Transcriptomic analysis of mouse T cells treated with IL7 in vitro revealed enhanced genomic pathways associated with protein translation. Improved translational ability was demonstrated by showing increased levels of protein expression after electroporation with mCherry mRNA in T cells cultured in the presence of IL7, but not with IL2 or IL15. These data show that IL7 selectively increases protein translation in T cells, and this property can be used to improve expression of tLNP-delivered mRNA in vivo.
Topics: Animals; Humans; Mice; CD8-Positive T-Lymphocytes; Interleukin-7; Liposomes; Nanoparticles; Protein Biosynthesis; RNA, Messenger; Mice, Inbred C57BL; Cells, Cultured; CD4-Positive T-Lymphocytes
PubMed: 38513098
DOI: 10.1073/pnas.2319856121 -
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