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Trends in Biochemical Sciences Aug 2020While targeting of proteins synthesized in the cytosol to any organelle is complex, mitochondria present the most challenging of destinations. First, import of... (Review)
Review
While targeting of proteins synthesized in the cytosol to any organelle is complex, mitochondria present the most challenging of destinations. First, import of nuclear-encoded proteins needs to be balanced with production of mitochondrial-encoded ones. Moreover, as mitochondria are divided into distinct subdomains, their proteins harbor a number of different targeting signals and biophysical properties. While translocation into the mitochondrial membranes has been well studied, the cytosolic steps of protein import remain poorly understood. Here, we review current knowledge on mRNA and protein targeting to mitochondria, as well as recent advances in our understanding of the cellular programs that respond to accumulation of mitochondrial precursor proteins in the cytosol, thus linking defects in targeting-capacity to signaling.
Topics: Cytosol; Heat-Shock Proteins; Homeostasis; Mitochondrial Proteins; Protein Biosynthesis; Protein Processing, Post-Translational; Protein Transport; Signal Recognition Particle; Signal Transduction
PubMed: 32409196
DOI: 10.1016/j.tibs.2020.04.001 -
Cold Spring Harbor Perspectives in... Jun 2019Most of the eukaryotic genome is pervasively transcribed, yielding hundreds to thousands of long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), some of which are... (Review)
Review
Most of the eukaryotic genome is pervasively transcribed, yielding hundreds to thousands of long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), some of which are well conserved during evolution. Functions have been described for a few lncRNAs and circRNAs but remain elusive for most. Both classes of RNAs play regulatory roles in translation by interacting with messenger RNAs (mRNAs), microRNAs (miRNAs), or mRNA-binding proteins (RBPs), thereby modulating translation in Moreover, although initially defined as noncoding, a number of lncRNAs and circRNAs have recently been reported to contain functional open reading frames (ORFs). Here, we review current understanding of the roles played by lncRNAs and circRNAs in protein synthesis and discuss challenges and open questions in the field.
Topics: Humans; Open Reading Frames; Protein Biosynthesis; RNA, Circular; RNA, Long Noncoding; RNA-Binding Proteins
PubMed: 30082465
DOI: 10.1101/cshperspect.a032680 -
Biochimica Et Biophysica Acta.... Sep 2021Genetic mutations that cause hereditary diseases usually affect the composition of the transcribed mRNA and its encoded protein, leading to instability of the mRNA... (Review)
Review
Genetic mutations that cause hereditary diseases usually affect the composition of the transcribed mRNA and its encoded protein, leading to instability of the mRNA and/or the protein. Sometimes, however, such mutations affect the synthesis, the processing or the translation of the mRNA, with similar disastrous effects. We here present an overview of mRNA synthesis, its posttranscriptional modification and its translation into protein. We then indicate which elements in these processes are known to be affected by pathogenic mutations, but we restrict our review to mutations in cis, in the DNA of the gene that encodes the affected protein. These mutations can be in enhancer or promoter regions of the gene, which act as binding sites for transcription factors involved in pre-mRNA synthesis. We also describe mutations in polyadenylation sequences and in splice site regions, exonic and intronic, involved in intron removal. Finally, we include mutations in the Kozak sequence in mRNA, which is involved in protein synthesis. We provide examples of genetic diseases caused by mutations in these DNA regions and refer to databases to help identify these regions. The over-all knowledge of mRNA synthesis, processing and translation is essential for improvement of the diagnosis of patients with genetic diseases.
Topics: Animals; Humans; Mutation; Protein Biosynthesis; Protein Processing, Post-Translational; RNA, Messenger
PubMed: 33971252
DOI: 10.1016/j.bbadis.2021.166166 -
Cell Systems Sep 2017Protein turnover maintains the recycling needs of the proteome, and its malfunction has been linked to aging and age-related diseases. However, not all proteins...
Protein turnover maintains the recycling needs of the proteome, and its malfunction has been linked to aging and age-related diseases. However, not all proteins turnover equally, and the factors that contribute to accelerate or slow down turnover are mostly unknown. We measured turnover rates for 3,160 proteins in exponentially growing yeast and analyzed their dependence on physical, functional, and genetic properties. We found that functional characteristics, including protein localization, complex membership, and connectivity, have greater effect on turnover than sequence elements. We also found that protein turnover and mRNA turnover are correlated. Analysis under nutrient perturbation and osmotic stress revealed that protein turnover highly depends on cellular state and is faster when proteins are being actively used. Finally, stress-induced changes in protein and transcript abundance correlated with changes in protein turnover. This study provides a resource of protein turnover rates and principles to understand the recycling needs of the proteome under basal conditions and perturbation.
Topics: Half-Life; Osmotic Pressure; Protein Biosynthesis; Protein Stability; Proteins; Proteolysis; Proteome; Proteomics; RNA Stability; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 28918244
DOI: 10.1016/j.cels.2017.08.008 -
Genes & Development Mar 2020ADP-ribosylation (ADPRylation) is a posttranslational modification of proteins discovered nearly six decades ago, but many important questions remain regarding its... (Review)
Review
ADP-ribosylation (ADPRylation) is a posttranslational modification of proteins discovered nearly six decades ago, but many important questions remain regarding its molecular functions and biological roles, as well as the activity of the ADP-ribose (ADPR) transferase enzymes (PARP family members) that catalyze it. Growing evidence indicates that PARP-mediated ADPRylation events are key regulators of the protein biosynthetic pathway, leading from rDNA transcription and ribosome biogenesis to mRNA synthesis, processing, and translation. In this review we describe the role of PARP proteins and ADPRylation in all facets of this pathway. PARP-1 and its enzymatic activity are key regulators of rDNA transcription, which is a critical step in ribosome biogenesis. An emerging role of PARPs in alternative splicing of mRNAs, as well as direct ADPRylation of mRNAs, highlight the role of PARP members in RNA processing. Furthermore, PARP activity, stimulated by cellular stresses, such as viral infections and ER stress, leads to the regulation of mRNA stability and protein synthesis through posttranscriptional mechanisms. Dysregulation of PARP activity in these processes can promote disease states. Collectively, these results highlight the importance of PARP family members and ADPRylation in gene regulation, mRNA processing, and protein abundance. Future studies in these areas will yield new insights into the fundamental mechanisms and a broader utility for PARP-targeted therapeutic agents.
Topics: ADP-Ribosylation; Animals; Gene Expression; Humans; Poly(ADP-ribose) Polymerases; Protein Biosynthesis; Protein Processing, Post-Translational; Proteostasis; RNA
PubMed: 32029452
DOI: 10.1101/gad.334433.119 -
Cell Cycle (Georgetown, Tex.) 2015Protein synthesis is one of the most energy consuming processes in the cell. The mammalian/mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that... (Review)
Review
Protein synthesis is one of the most energy consuming processes in the cell. The mammalian/mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that integrates a multitude of extracellular signals and intracellular cues to drive growth and proliferation. mTOR activity is altered in numerous pathological conditions, including metabolic syndrome and cancer. In addition to its well-established role in regulating mRNA translation, emerging studies indicate that mTOR modulates mitochondrial functions. In mammals, mTOR coordinates energy consumption by the mRNA translation machinery and mitochondrial energy production by stimulating synthesis of nucleus-encoded mitochondria-related proteins including TFAM, mitochondrial ribosomal proteins and components of complexes I and V. In this review, we highlight findings that link mTOR, mRNA translation and mitochondrial functions.
Topics: Animals; Cell Proliferation; Humans; Mitochondria; Models, Biological; Protein Biosynthesis; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 25590164
DOI: 10.4161/15384101.2014.991572 -
Oxidative Medicine and Cellular... 2022
Topics: Autophagy; Protein Biosynthesis
PubMed: 35340207
DOI: 10.1155/2022/9792132 -
Neuropsychopharmacology : Official... Jan 2016
Review
Topics: Animals; Humans; Protein Biosynthesis; RNA; Real-Time Polymerase Chain Reaction; Sequence Analysis, RNA
PubMed: 26657954
DOI: 10.1038/npp.2015.262 -
Physiology (Bethesda, Md.) Jan 2019The ribosome is the enzymatic macromolecular machine responsible for protein synthesis. The rates of protein synthesis are primarily dependent on translational... (Review)
Review
The ribosome is the enzymatic macromolecular machine responsible for protein synthesis. The rates of protein synthesis are primarily dependent on translational efficiency and capacity. Ribosome biogenesis has emerged as an important regulator of skeletal muscle growth and maintenance by altering the translational capacity of the cell. Here, we provide evidence to support a central role for ribosome biogenesis in skeletal muscle growth during postnatal development and in response to resistance exercise training. Furthermore, we discuss the cellular signaling pathways regulating ribosome biogenesis, discuss how myonuclear accretion affects translational capacity, and explore future areas of investigation within the field.
Topics: Animals; Humans; Hypertrophy; Muscle Development; Muscle, Skeletal; Protein Biosynthesis; Resistance Training; Ribosomes; Signal Transduction
PubMed: 30540235
DOI: 10.1152/physiol.00034.2018 -
Brain Research Aug 2018Research in the past decades has unfolded the multifaceted role of Fragile X mental retardation protein (FMRP) and how its absence contributes to the pathophysiology of... (Review)
Review
Research in the past decades has unfolded the multifaceted role of Fragile X mental retardation protein (FMRP) and how its absence contributes to the pathophysiology of Fragile X syndrome (FXS). Excess signaling through group 1 metabotropic glutamate receptors is commonly observed in mouse models of FXS, which in part is attributed to dysregulated translation and downstream signaling. Considering the wide spectrum of cellular and physiologic functions that loss of FMRP can affect in general, it may be advantageous to pursue disease mechanism based treatments that directly target translational components or signaling factors that regulate protein synthesis. Various FMRP targets upstream and downstream of the translational machinery are therefore being investigated to further our understanding of the molecular mechanism of RNA and protein synthesis dysregulation in FXS as well as test their potential role as therapeutic interventions to alleviate FXS associated symptoms. In this review, we will broadly discuss recent advancements made towards understanding the role of FMRP in translation regulation, new pre-clinical animal models with FMRP targets located at different levels of the translational and signal transduction pathways for therapeutic intervention as well as future use of stem cells to model FXS associated phenotypes.
Topics: Animals; Dendrites; Disease Models, Animal; Fragile X Mental Retardation Protein; Fragile X Syndrome; Gene Expression Regulation; Humans; Protein Biosynthesis; RNA, Messenger; Receptors, Metabotropic Glutamate; Signal Transduction
PubMed: 29653083
DOI: 10.1016/j.brainres.2018.04.008