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Journal of Hepatology Aug 2018Hepatocytes synthesise the majority of serum proteins. This production occurs in the endoplasmic reticulum (ER) and is adjusted by complex local and systemic regulatory... (Review)
Review
Hepatocytes synthesise the majority of serum proteins. This production occurs in the endoplasmic reticulum (ER) and is adjusted by complex local and systemic regulatory mechanisms. Accordingly, serum levels of hepatocyte-made proteins constitute important biomarkers that reflect both systemic processes and the status of the liver. For example, C-reactive protein is an established marker of inflammatory reaction, whereas transferrin emerges as a liver stress marker and an attractive mortality predictor. The high protein flow through the ER poses a continuous challenge that is handled by a complex proteostatic network consisting of ER folding machinery, ER stress response, ER-associated degradation and autophagy. Various disorders disrupt this delicate balance and result in protein accumulation in the ER. These include chronic hepatitis B infection with overproduction of hepatitis B surface antigen or inherited alpha1-antitrypsin deficiency that give rise to ground glass hepatocytes and alpha1-antitrypsin aggregates, respectively. We review these ER storage disorders and their downstream consequences. The interaction between proteotoxic stress and other ER challenges such as lipotoxicity is also discussed. Collectively, this article aims to sharpen our view of liver hepatocytes as the central hubs of protein metabolism.
Topics: Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Hepatocytes; Humans; Protein Biosynthesis; Proteins
PubMed: 29709680
DOI: 10.1016/j.jhep.2018.04.018 -
Genetics May 2016In this review, we provide an overview of protein synthesis in the yeast Saccharomyces cerevisiae The mechanism of protein synthesis is well conserved between yeast and... (Review)
Review
In this review, we provide an overview of protein synthesis in the yeast Saccharomyces cerevisiae The mechanism of protein synthesis is well conserved between yeast and other eukaryotes, and molecular genetic studies in budding yeast have provided critical insights into the fundamental process of translation as well as its regulation. The review focuses on the initiation and elongation phases of protein synthesis with descriptions of the roles of translation initiation and elongation factors that assist the ribosome in binding the messenger RNA (mRNA), selecting the start codon, and synthesizing the polypeptide. We also examine mechanisms of translational control highlighting the mRNA cap-binding proteins and the regulation of GCN4 and CPA1 mRNAs.
Topics: Gene Expression Regulation, Fungal; Peptide Chain Elongation, Translational; Peptide Chain Termination, Translational; Protein Biosynthesis; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 27183566
DOI: 10.1534/genetics.115.186221 -
Amino Acids Dec 2021Proline is a non-essential amino acid with key roles in protein structure/function and maintenance of cellular redox homeostasis. It is available from dietary sources,... (Review)
Review
Proline is a non-essential amino acid with key roles in protein structure/function and maintenance of cellular redox homeostasis. It is available from dietary sources, generated de novo within cells, and released from protein structures; a noteworthy source being collagen. Its catabolism within cells can generate ATP and reactive oxygen species (ROS). Recent findings suggest that proline biosynthesis and catabolism are essential processes in disease; not only due to the role in new protein synthesis as part of pathogenic processes but also due to the impact of proline metabolism on the wider metabolic network through its significant role in redox homeostasis. This is particularly clear in cancer proliferation and metastatic outgrowth. Nevertheless, the precise identity of the drivers of cellular proline catabolism and biosynthesis, and the overall cost of maintaining appropriate balance is not currently known. In this review, we explore the major drivers of proline availability and consumption at a local and systemic level with a focus on cancer. Unraveling the main factors influencing proline metabolism in normal physiology and disease will shed light on new effective treatment strategies.
Topics: Animals; Homeostasis; Humans; Neoplasms; Oxidation-Reduction; Proline; Protein Biosynthesis; Reactive Oxygen Species
PubMed: 34291343
DOI: 10.1007/s00726-021-03051-2 -
Biochimica Et Biophysica Acta.... Jan 2017Among mitochondrial lipids, cardiolipin occupies a unique place. It is the only phospholipid that is specific to mitochondria and although it is merely a minor... (Review)
Review
Among mitochondrial lipids, cardiolipin occupies a unique place. It is the only phospholipid that is specific to mitochondria and although it is merely a minor component, accounting for 10-20% of the total phospholipid content, cardiolipin plays an important role in the molecular organization, and thus the function of the cristae. This review covers the formation of cardiolipin, a phospholipid dimer containing two phosphatidyl residues, and its assembly into mitochondrial membranes. While a large body of literature exists on this topic, the review focuses on papers that appeared in the past three years. This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum.
Topics: Animals; Cardiolipins; Humans; Mitochondria; Mitochondrial Membranes; Phospholipids; Protein Biosynthesis
PubMed: 27556952
DOI: 10.1016/j.bbalip.2016.08.010 -
Current Opinion in Genetics &... Feb 2018The processes by which the canonical protein synthesis machinery is modified by environmental stresses to allow healthy cells to respond to external conditions to... (Review)
Review
The processes by which the canonical protein synthesis machinery is modified by environmental stresses to allow healthy cells to respond to external conditions to maintain homeostasis, are frequently hijacked by tumour cells to enhance their survival. Two major stress response pathways that play a major role in this regard are the unfolded protein response (UPR) and the DNA damage response (DDR). Recent data have shown that key proteins which coordinate post-transcriptional control, and which are regulated by signalling through the UPR and DDR, are upregulated in cancers and that targeting these proteins/pathways will provide new therapeutic avenues for cancer treatments.
Topics: Animals; DNA Repair; Gene Expression Regulation; Humans; Neoplasms; Protein Biosynthesis; Unfolded Protein Response
PubMed: 29100210
DOI: 10.1016/j.gde.2017.10.006 -
Biochemical Society Transactions Dec 2022Protein synthesis is dysregulated in the majority of cancers and this process therefore provides a good therapeutic target. Many novel anti-cancer agents are directed to... (Review)
Review
Protein synthesis is dysregulated in the majority of cancers and this process therefore provides a good therapeutic target. Many novel anti-cancer agents are directed to target the initiation stage of translation, however, translation elongation also holds great potential as a therapeutic target. The elongation factor eIF5A that assists the formation of peptidyl bonds during the elongation process is of considerable interest in this regard. Overexpression of eIF5A has been linked with the development of a variety of cancers and inhibitors of the molecule have been proposed for anti-cancer clinical applications. eIF5A is the only protein in the cell that contains the post-translational modification hypusine. Hypusination is a two-step enzymatic process catalysed by the Deoxyhypusine Synthase (DHPS) and Deoxyhypusine Hydroxylase (DOHH). In addition, eIF5A can be acetylated by p300/CBP-associated factor (PCAF) which leads to translocation of the protein to the nucleus and its deactivation. In addition to the nucleus, eIF5A has been found in the mitochondria and the endoplasmic reticulum (ER) with eIF5A localisation related to function from regulation of mitochondrial activity and apoptosis to maintenance of ER integrity and control of the unfolded protein response (UPR). Given the pleiotropic functions of eIF5A and by extension the hypusination enzymes, this system is being considered as a target for a range of cancers including multiple myeloma, B-Cell lymphoma, and neuroblastoma. In this review, we explore the role of eIF5A and discuss the therapeutic strategies that are currently developing both in the pre- and the clinical stage.
Topics: Peptide Initiation Factors; Protein Biosynthesis; Protein Processing, Post-Translational; Apoptosis; Neoplasms
PubMed: 36511302
DOI: 10.1042/BST20221035 -
Anatomical Record (Hoboken, N.J. : 2007) Dec 2018Actin is one of the most abundant intracellular proteins, essential in every eukaryotic cell type. Actin plays key roles in tissue morphogenesis, cell adhesion, muscle... (Review)
Review
Actin is one of the most abundant intracellular proteins, essential in every eukaryotic cell type. Actin plays key roles in tissue morphogenesis, cell adhesion, muscle contraction, and developmental reprogramming. Most actin studies have focused on its regulation at the protein level, either directly or through differential interactions with over a hundred intracellular binding partners. However, numerous studies emerging in recent years demonstrate specific types of nucleotide-level regulation that strongly affect non-muscle actins during cell migration and adhesion and are potentially applicable to other members of the actin family. This regulation involves zipcode-mediated actin mRNA targeting to the cell periphery, proposed to mediate local synthesis of actin at the cell leading edge, as well as the recently discovered N-terminal arginylation that specifically targets non-muscle β-actin via a nucleotide-dependent mechanism. Moreover, a study published this year suggests that actin's essential roles at the organismal level may be entirely nucleotide-dependent. This review summarizes the emerging data on actin's nucleotide-level regulation. Anat Rec, 301:1991-1998, 2018. © 2018 Wiley Periodicals, Inc.
Topics: Actin Cytoskeleton; Actins; Amino Acid Sequence; Animals; Humans; Protein Biosynthesis; Protein Processing, Post-Translational; RNA Interference
PubMed: 30312009
DOI: 10.1002/ar.23958 -
Trends in Genetics : TIG Nov 2018The ability of cells to grow and divide, differentiate and function, and even senesce is dependent on the fine-tuning of both gene and protein expression. Protein... (Review)
Review
The ability of cells to grow and divide, differentiate and function, and even senesce is dependent on the fine-tuning of both gene and protein expression. Protein concentration in the cell is regulated not only at the transcriptional and post-translational levels, but also at the level of translation. Ribosomes, the molecular machines behind translation, were once considered to be an invariant driving force behind protein expression. However, studies over the past decade paint a rather different picture; namely, that ribosomes constitute an additional layer of regulatory control that might define which subsets of mRNAs are translated, to what extent, and to what purpose. Recent works summarized herein directly implicate ribosome heterogeneity and, in particular, ribosomal protein (RP) paralog specificity in regulating mRNA translation and control of the cellular translatome.
Topics: Protein Biosynthesis; RNA, Messenger; Ribosomal Proteins; Ribosomes
PubMed: 30195580
DOI: 10.1016/j.tig.2018.08.004 -
The New England Journal of Medicine Mar 2023
Review
Topics: Humans; Gene Expression Regulation; Neurodegenerative Diseases; Protein Biosynthesis; RNA; RNA, Messenger
PubMed: 36920757
DOI: 10.1056/NEJMra2215795 -
Journal of Molecular Biology May 2020A large part of mammalian physiology and behaviour shows regular daily variations. This temporal organisation is driven by the activity of an endogenous circadian clock,... (Review)
Review
A large part of mammalian physiology and behaviour shows regular daily variations. This temporal organisation is driven by the activity of an endogenous circadian clock, whose molecular basis consists of diurnal waves in gene expression. Circadian transcription is the major driver of these rhythms, yet post-transcriptional mechanisms, some of which occur in response to systemic cues and in a tissue-specific fashion, have central roles in ultimately establishing the oscillatory gene expression programme as well. Regulatory control that occurs at the level of translation is emerging as an important player in the generation and modulation of protein accumulation rhythms. As a mechanism, translation lies at a privileged position to integrate genetically encoded rhythmic signals with other, external and internal stimuli, including nutrient-derived cues. In this review, we summarise our current knowledge of how diurnal control of translation affects both bulk protein levels and gene-specific protein biosynthesis. We discuss mechanisms of regulation, in particular with regard to the complex interplay between circadian cycles and feeding/fasting cycles, as well as emerging roles for upstream open reading frames in clock control.
Topics: Animals; Circadian Clocks; Circadian Rhythm; Humans; Mammals; Protein Biosynthesis; Transcription, Genetic
PubMed: 32246961
DOI: 10.1016/j.jmb.2020.03.023