scholarly journals Metabolic Reprogramming of Liver Fibrosis

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3604
Author(s):  
M. Eugenia Delgado ◽  
Beatriz I. Cárdenas ◽  
Núria Farran ◽  
Mercedes Fernandez
Keyword(s):  
Liver Fibrosis ◽  
Cellular Response ◽  
Metabolic Regulation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Metabolic Reprogramming ◽  
Common Mechanism ◽  
Special Focus ◽  
Metabolic Switch ◽  
Main Components

Liver fibrosis is an excessive and imbalanced deposition of fibrous extracellular matrix (ECM) that is associated with the hepatic wound-healing response. It is also the common mechanism that contributes to the impairment of the liver function that is observed in many chronic liver diseases (CLD). Despite the efforts, no effective therapy against fibrosis exists yet. Worryingly, due to the growing obesity pandemic, fibrosis incidence is on the rise. Here, we aim to summarize the main components and mechanisms involved in the progression of liver fibrosis, with special focus on the metabolic regulation of key effectors of fibrogenesis, hepatic stellate cells (HSCs), and their role in the disease progression. Hepatic cells that undergo metabolic reprogramming require a tightly controlled, fine-tuned cellular response, allowing them to meet their energetic demands without affecting cellular integrity. Here, we aim to discuss the role of ribonucleic acid (RNA)-binding proteins (RBPs), whose dynamic nature being context- and stimuli-dependent make them very suitable for the fibrotic situation. Thus, we will not only summarize the up-to-date literature on the metabolic regulation of HSCs in liver fibrosis, but also on the RBP-dependent post-transcriptional regulation of this metabolic switch that results in such important consequences for the progression of fibrosis and CLD.

scholarly journals Ras Suppresses TXNIP Expression by Restricting Ribosome Translocation

2018 ◽  
Author(s):  
Zhizhou Ye ◽  
Donald E. Ayer
Keyword(s):  
Protein Synthesis ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Aerobic Glycolysis ◽  
Protein Translation ◽  
Underlying Mechanism ◽  
Metabolic Reprogramming ◽  
Coding Region ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein

ABSTRACTOncogenic Ras upregulates aerobic glycolysis to meet the bioenergetic and biosynthetic demands of rapidly growing cells. In contrast, Thioredoxin interacting protein (TXNIP) is a potent inhibitor of glucose uptake and is frequently downregulated in human cancers. Our lab previously discovered that Ras activation suppresses TXNIP transcription and translation. In this report, we developed a system to study how Ras affects TXNIP translation in the absence of transcriptional affects. We show that whereas Ras drives a global increase in protein translation, it suppresses TXNIP protein synthesis by reducing the rate at which ribosomes transit the coding region of TXNIP mRNA. To investigate the underlying mechanism(s), we randomized or optimized the codons in the TXNIP message without altering the TXNIP primary amino acid sequence. Translation from these mRNA variants is still repressed by Ras, intimating that mRNA secondary structure, miRNAs, RNA binding proteins, or codon usage do not contribute to the blockade of TXNIP synthesis. Rather, we show that the N-terminus of the growing TXNIP polypeptide is the target for Ras-dependent translational repression. Our work demonstrates how Ras suppresses TXNIP translation elongation in the face of a global upregulation of protein synthesis and provides new insight into Ras-dependent metabolic reprogramming.

scholarly journals SPLICING ABNORMALITIES IN MYOTONIC DYSTROPHIES

2014 ◽  
pp. 9-23
Author(s):  
Denis Furling
Keyword(s):  
Clinical Features ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Cardiac Conduction ◽  
Nuclear Accumulation ◽  
Common Mechanism ◽  
Inherited Disease ◽  
Loss Of Function ◽  
Coding Region ◽  
Membrane Structures

Myotonic dystrophy of type 1 (DM1) is one of the most common muscular dystrophy in adults characterized by progressive muscle wasting and weakness, myotonia, cardiac conduction defects, alteration in cognitive functions as well as several other multisystemic symptoms. DM1 is an autosomal dominant inherited disease caused by an unstable CTG expansion ranging from ~50 to more than 1,000 repeats in the 3’ non-coding region of the DMPK gene. Expression of DMPK RNAs with expanded CUG repeats supports a toxic RNA gain-of-function as a pathologic mechanism for DM1. A similar or common mechanism may also be involved in DM type 2 that is caused by CCTG expansion in the first intron of the CNP (ZNF9) gene and shares similar clinical features with DM1 disease. In both myotonic dystrophies, nuclear accumulation of pathogenic CUG/CCUGexp-RNAs alters the activities of the RNA binding proteins such as MBNL1 and CUG-BP1 that leads to alternative splicing mis-regulation of a numerous of transcripts in DM tissues and ultimately, to clinical features of the disease. An overview of the DM splicing mis-regulation will be presented, with focus on mis- regulation of the BIN1 mRNA. In muscle, BIN1 plays an important role in tubular invaginations of the plasma membrane and is required for biogenesis of T-tubules, which are specialized membrane structures essential for excitation-contraction coupling. BIN1 splicing mis-regulation in DM patients due to MBNL1 loss-of-function results in the expression of an inactive form of BIN1 deprived of phosphoinositide-binding and membrane-tubulating activities. Reproducing similar BIN1 mis-splicing defect in the muscles of wild type mice is sufficient to promote T-tubule alterations and muscle strength decrease, suggesting that alteration of BIN1 splicing may contributes to muscle weakness, a prominent feature in DM.

scholarly journals New Faces of old Friends: Emerging new Roles of RNA-Binding Proteins in the DNA Double-Strand Break Response

2021 ◽  
Vol 8 ◽  
Author(s):  
Julie A. Klaric ◽  
Stas Wüst ◽  
Stephanie Panier
Keyword(s):  
Cellular Response ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Genome Instability ◽  
Strand Break ◽  
Dna Lesions ◽  
Cell Cycle Checkpoints ◽  
Dna Double Strand Breaks ◽  
Dna Strand

DNA double-strand breaks (DSBs) are highly cytotoxic DNA lesions. To protect genomic stability and ensure cell homeostasis, cells mount a complex signaling-based response that not only coordinates the repair of the broken DNA strand but also activates cell cycle checkpoints and, if necessary, induces cell death. The last decade has seen a flurry of studies that have identified RNA-binding proteins (RBPs) as novel regulators of the DSB response. While many of these RBPs have well-characterized roles in gene expression, it is becoming increasingly clear that they also have non-canonical functions in the DSB response that go well beyond transcription, splicing and mRNA processing. Here, we review the current understanding of how RBPs are integrated into the cellular response to DSBs and describe how these proteins directly participate in signal transduction, amplification and repair at damaged chromatin. In addition, we discuss the implications of an RBP-mediated DSB response for genome instability and age-associated diseases such as cancer and neurodegeneration.

scholarly journals DEAD Box 1 Facilitates Removal of RNA and Homologous Recombination at DNA Double-Strand Breaks

2016 ◽  
Vol 36 (22) ◽  
pp. 2794-2810 ◽  
Author(s):  
Lei Li ◽  
Devon R. Germain ◽  
Ho-Yin Poon ◽  
Matthew R. Hildebrandt ◽  
Elizabeth A. Monckton ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Cellular Response ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Repair Process ◽  
Double Strand Breaks ◽  
Dsb Repair ◽  
Strand Breaks ◽  
Dead Box ◽  
End Resection

Although RNA and RNA-binding proteins have been linked to double-strand breaks (DSBs), little is known regarding their roles in the cellular response to DSBs and, if any, in the repair process. Here, we provide direct evidence for the presence of RNA-DNA hybrids at DSBs and suggest that binding of RNA to DNA at DSBs may impact repair efficiency. Our data indicate that the RNA-unwinding protein DEAD box 1 (DDX1) is required for efficient DSB repair and cell survival after ionizing radiation (IR), with depletion of DDX1 resulting in reduced DSB repair by homologous recombination (HR). While DDX1 is not essential for end resection, a key step in homology-directed DSB repair, DDX1 is required for maintenance of the single-stranded DNA once generated by end resection. We show that transcription deregulation has a significant effect on DSB repair by HR in DDX1-depleted cells and that RNA-DNA duplexes are elevated at DSBs in DDX1-depleted cells. Based on our combined data, we propose a role for DDX1 in resolving RNA-DNA structures that accumulate at DSBs located at sites of active transcription. Our findings point to a previously uncharacterized requirement for clearing RNA at DSBs for efficient repair by HR.

scholarly journals Targeting of Post-Transcriptional Regulation as Treatment Strategy in Acute Leukemia

2020 ◽  
Author(s):  
Paulina Podszywalow-Bartnicka ◽  
Magdalena Wolczyk ◽  
Katarzyna Piwocka
Keyword(s):  
Transcriptional Regulation ◽  
Acute Leukemia ◽  
Cancer Cells ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Protein Profile ◽  
Cellular Protein ◽  
Special Focus ◽  
Transcriptional Level ◽  
Post Transcriptional Regulation

Post-transcriptional regulation is an important step of gene expression that allows to fine-tune the cellular protein profile (so called proteome) according to the current demands. That mechanism has been developed to aid survival under stress conditions, however it occurs to be hijacked by cancer cells. Adjustment of the protein profile remodels signaling in cancer cells to adapt to therapeutic treatment, thereby enabling persistence despite unfavorable environment or accumulating mutations. The proteome is shaped at the post-transcriptional level by numerous mechanisms such as alternative splicing, mRNA modifications and triage by RNA binding proteins, change of ribosome composition or signaling, which altogether regulate the translation process. This chapter is an overview of the translation disturbances found in leukemia and their role in development of the disease, with special focus on the possible therapeutic strategies tested in acute leukemia which target elements of those regulatory mechanisms.

scholarly journals Ras Suppresses TXNIP Expression by Restricting Ribosome Translocation

2018 ◽  
Vol 38 (20) ◽  
Author(s):  
Zhizhou Ye ◽  
Donald E. Ayer
Keyword(s):  
Protein Synthesis ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Aerobic Glycolysis ◽  
Protein Translation ◽  
Underlying Mechanism ◽  
Metabolic Reprogramming ◽  
Coding Region ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein

ABSTRACT Oncogenic Ras upregulates aerobic glycolysis to meet the bioenergetic and biosynthetic demands of rapidly growing cells. In contrast, thioredoxin-interacting protein (TXNIP) is a potent inhibitor of glucose uptake and is frequently downregulated in human cancers. Our laboratory previously discovered that Ras activation suppresses TXNIP transcription and translation. In this study, we developed a system to study how Ras affects TXNIP translation in the absence of transcriptional effects. We show that whereas Ras drives a global increase in protein translation, it suppresses TXNIP protein synthesis by reducing the rate at which ribosomes transit the coding region of TXNIP mRNA. To investigate the underlying mechanism(s), we randomized or optimized the codons in the TXNIP message without altering the TXNIP primary amino acid sequence. Translation from these mRNA variants was still repressed by Ras, implying that mRNA secondary structure, microRNAs (miRNAs), RNA binding proteins, or codon usage does not contribute to the blockade of TXNIP synthesis. Rather, we show that the N terminus of the growing TXNIP polypeptide is the target for Ras-dependent translational repression. Our work demonstrates how Ras suppresses TXNIP translation elongation in the face of a global upregulation of protein synthesis and provides new insight into Ras-dependent metabolic reprogramming.

scholarly journals Screening of metabolic modulators identifies new strategies to target metabolic reprogramming in melanoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Cecilie Abildgaard ◽  
Salvatore Rizza ◽  
Helle Christiansen ◽  
Steffen Schmidt ◽  
Christina Dahl ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Cellular Response ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Braf Inhibitor ◽  
Melanoma Cells ◽  
Metabolic Reprogramming ◽  
Pyruvate Dehydrogenase Kinase ◽  
Metabolic Switch ◽  
Growth Inhibitory

AbstractThe prognosis of metastatic melanoma remains poor due to de novo or acquired resistance to immune and targeted therapies. Previous studies have shown that melanoma cells have perturbed metabolism and that cellular metabolic pathways represent potential therapeutic targets. To support the discovery of new drug candidates for melanoma, we examined 180 metabolic modulators, including phytochemicals and anti-diabetic compounds, for their growth-inhibitory activities against melanoma cells, alone and in combination with the BRAF inhibitor vemurafenib. Two positive hits from this screen, 4-methylumbelliferone (4-MU) and ursolic acid (UA), were subjected to validation and further characterization. Metabolic analysis showed that 4-MU affected cellular metabolism through inhibition of glycolysis and enhanced the effect of vemurafenib to reduce the growth of melanoma cells. In contrast, UA reduced mitochondrial respiration, accompanied by an increase in the glycolytic rate. This metabolic switch potentiated the growth-inhibitory effect of the pyruvate dehydrogenase kinase inhibitor dichloroacetate. Both drug combinations led to increased production of reactive oxygen species, suggesting the involvement of oxidative stress in the cellular response. These results support the potential use of metabolic modulators for combination therapies in cancer and may encourage preclinical validation and clinical testing of such treatment strategies in patients with metastatic melanoma.

scholarly journals Long Noncoding RNA UCA1 Promotes Glutamine-Driven Anaplerosis of Bladder Cancer by Interacting With hnRNP I/L to Upregulate GPT2 Expression

2020 ◽  
Author(s):  
Hua Zhao ◽  
Wenjing Wu ◽  
Xu Li ◽  
Wei Chen
Keyword(s):  
Bladder Cancer ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Metabolic Flux ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Tca Cycle ◽  
Metabolic Reprogramming ◽  
Luciferase Reporter ◽  
Flux Analysis

Abstract Background: Glutamine-driven anaplerosis maintains the tricarboxylic acid (TCA) cycle by replenishing its carbon source of intermediates with the glutamine-derived carbons in cancer cells. Long noncoding RNA urothelial cancer associated 1 (UCA1), initially identified in bladder cancer, is associated with multiple cellular processes, including metabolic reprogramming. However, its characteristics in the anaplerosis context of bladder cancer (BLCA) remains elusive. Methods: The mechanism of UCA1 bound to and facilitated the combination of hnRNP I/L to the promoter of GPT2 gene was investigated by RNA pulldown, qRT-PCR, western blot, dual luciferase reporter assays, immunohistochemical staining, chromatin immunoprecipitation and chromatin isolation by RNA purification. Metabolomics analysis and metabolic flux analysis were conducted to assess the effects of UCA1, hnRNP I/L, and GPT2 on metabolic reprogramming of BLCA.Results: We identified UCA1 as a binding partner of heterogeneous nuclear ribonucleoproteins (hnRNPs) I and L, RNA-binding proteins with no previously known role in metabolic reprogramming. UCA1 and hnRNP I/L profoundly affected glycolysis, TCA cycle, glutaminolysis, and viability of BLCA cells. Importantly, UCA1 specifically bound to and facilitated the combination of hnRNP I/L to the promoter of glutamic pyruvate transaminase 2 (GPT2) gene, resulting in upregulated expression of GPT2 and enhanced glutamine-derived carbons in the TCA cycle. We also systematically confirmed the influence of UCA1, hnRNP I/L, and GPT2 on metabolism and proliferation via glutamine-driven anaplerosis in BLCA cells. Conclusions: Our study reveals the critical mechanism by which UCA1 forms a functional UCA1-hnRNP I/L complex that upregulates GPT2 expression to promote glutamine-driven TCA cycle anaplerosis, providing novel evidence that lncRNA regulates metabolic reprogramming in tumor cells.

scholarly journals Post-transcriptional control of gene expression following stress: the role of RNA-binding proteins

2017 ◽  
Vol 45 (4) ◽  
pp. 1007-1014 ◽  
Author(s):  
Robert Harvey ◽  
Veronica Dezi ◽  
Mariavittoria Pizzinga ◽  
Anne E. Willis
Keyword(s):  
Protein Synthesis ◽  
Mammalian Cells ◽  
Cellular Response ◽  
Transcriptional Control ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Major Influence ◽  
Functional Protein ◽  
Control Of Gene Expression

The ability of mammalian cells to modulate global protein synthesis in response to cellular stress is essential for cell survival. While control of protein synthesis is mediated by the regulation of eukaryotic initiation and elongation factors, RNA-binding proteins (RBPs) provide a crucial additional layer to post-transcriptional regulation. RBPs bind specific RNA through conserved RNA-binding domains and ensure that the information contained within the genome and transcribed in the form of RNA is exported to the cytoplasm, chemically modified, and translated prior to folding into a functional protein. Thus, this group of proteins, through mediating translational reprogramming, spatial reorganisation, and chemical modification of RNA molecules, have a major influence on the robust cellular response to external stress and toxic injury.

scholarly journals Cytosolic aspartate aminotransferase moonlights as a ribosome binding modulator of Gcn2 activity during oxidative stress

2021 ◽  
Author(s):  
Robert A. Crawford ◽  
Mark P. Ashe ◽  
Simon J. Hubbard ◽  
Graham D. Pavitt
Keyword(s):  
Oxidative Stress ◽  
Translational Control ◽  
Aspartate Aminotransferase ◽  
Ribosomal Proteins ◽  
Translational Regulation ◽  
Cellular Response ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Stress Sensitivity ◽  
Yeast Cells

AbstractRegulation of translation is a fundamental facet of the cellular response to rapidly changing external conditions. Specific RNA-binding proteins (RBPs) co-ordinate the translational regulation of distinct mRNA cohorts during stress. To identify RBPs with previously under-appreciated roles in translational control, we used polysome profiling and mass spectrometry to identify and quantify proteins associated with translating ribosomes in unstressed yeast cells and during oxidative stress and amino acid starvation, which both induce the integrated stress response (ISR). Over 800 proteins were identified across polysome gradient fractions, including ribosomal proteins, translation factors and many others without previously described translation-related roles, including numerous metabolic enzymes. We identified variations in patterns of polysome enrichment in both unstressed and stressed cells and identified proteins enriched in heavy polysomes during stress. Genetic screening of polysome-enriched RBPs identified the cytosolic aspartate aminotransferase, Aat2, as a ribosome-associated protein whose deletion conferred growth sensitivity to oxidative stress. Loss of Aat2 caused aberrantly high activation of the ISR via enhanced eIF2α phosphorylation and GCN4 activation. Importantly, non-catalytic AAT2 mutants retained polysome association and did not show heightened stress sensitivity. Aat2 therefore has a separate ribosome-associated translational regulatory or ‘moonlighting’ function that modulates the ISR independent of its aspartate aminotransferase activity.

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