scholarly journals FOXO1 controls protein synthesis and transcript abundance of mutant polyglutamine proteins, preventing protein aggregation

2021 ◽  
Author(s):  
Gabriel Vasata Furtado ◽  
Jing Yang ◽  
Di Wu ◽  
Christos I Papagiannopoulos ◽  
Hanna M Terpstra ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Protein Degradation ◽  
Transcript Abundance ◽  
Cag Repeat ◽  
Mutant Proteins ◽  
Protein Levels ◽  
Polyq Protein ◽  
Elevated Expression ◽  
Aberrant Rna ◽  
Mrna Binding

Abstract FOXO1, a transcription factor downstream of the insulin/insulin like growth factor axis has been linked to protein degradation. Elevated expression of FOXO orthologs can also prevent aggregation of CAG-repeat disease causing polyglutamine (polyQ) proteins but whether FOXO1 targets mutant proteins for degradation is unclear. Here we show that increased expression of FOXO1 prevents toxic polyQ aggregation in human cells while reducing FOXO1 levels has the opposite effect and accelerates it. Although FOXO1 indeed stimulates autophagy, its effect on polyQ aggregation is independent of autophagy, UPS mediated protein degradation and is not due to a change in mutant polyQ protein turnover. Instead FOXO1 specifically downregulates protein synthesis rates from expanded pathogenic CAG repeat transcripts. FOXO1 orchestrates a change in the composition of proteins that occupy mutant expanded CAG transcripts, including the recruitment of IGF2BP3. This mRNA binding protein enables a FOXO1 driven decrease in pathogenic expanded CAG transcript- and protein levels, thereby reducing the initiation of amyloidogenesis. Our data thus demonstrate that FOXO1 not only preserves protein homeostasis at multiple levels, but also reduces accumulation of aberrant RNA species that may co-contribute to the toxicity in CAG-repeat diseases.

scholarly journals The switch-like expression of heme-regulated kinase 1 mediates neuronal proteostasis following proteasome inhibition

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Beatriz Alvarez-Castelao ◽  
Susanne tom Dieck ◽  
Claudia M Fusco ◽  
Paul Donlin-Asp ◽  
Julio D Perez ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Protein Degradation ◽  
Kinase Inhibitor ◽  
Neuronal Cell ◽  
Proteasome Inhibition ◽  
Ubiquitin Proteasome System ◽  
Degradation Pathway ◽  
Major Protein ◽  
Protein Levels ◽  
Eif2α Phosphorylation

We examined the feedback between the major protein degradation pathway, the ubiquitin-proteasome system (UPS), and protein synthesis in rat and mouse neurons. When protein degradation was inhibited, we observed a coordinate dramatic reduction in nascent protein synthesis in neuronal cell bodies and dendrites. The mechanism for translation inhibition involved the phosphorylation of eIF2α, surprisingly mediated by eIF2α kinase 1, or heme-regulated kinase inhibitor (HRI). Under basal conditions, neuronal expression of HRI is barely detectable. Following proteasome inhibition, HRI protein levels increase owing to stabilization of HRI and enhanced translation, likely via the increased availability of tRNAs for its rare codons. Once expressed, HRI is constitutively active in neurons because endogenous heme levels are so low; HRI activity results in eIF2α phosphorylation and the resulting inhibition of translation. These data demonstrate a novel role for neuronal HRI that senses and responds to compromised function of the proteasome to restore proteostasis.

PHOTACs Enable Optical Control of Protein Degradation

2019 ◽  
Author(s):  
Martin Reynders ◽  
Bryan Matsuura ◽  
Marleen Bérouti ◽  
Daniele Simoneschi ◽  
Antonio Marzio ◽  
...  
Keyword(s):  
Protein Degradation ◽  
E3 Ligase ◽  
Optical Control ◽  
Cellular Proteins ◽  
Bifunctional Molecules ◽  
Protein Levels ◽  
Lead Compounds ◽  
Subsequent Degradation ◽  
Temporal And Spatial ◽  
Precision Therapeutics

<p><i>PROTACs (proteolysis targeting chimeras) are bifunctional molecules that tag proteins for ubiquitylation by an E3 ligase complex and subsequent degradation by the proteasome. They have emerged as powerful tools to control the levels of specific cellular proteins and are on the verge of being clinically used. We now introduce photoswitchable PROTACs that can be activated with the temporal and spatial precision that light provides. These trifunctional molecules, which we named PHOTACs, consist of a ligand for an E3 ligase, a photoswitch, and a ligand for a protein of interest. We demonstrate this concept by using PHOTACs that target either BET family proteins (BRD2,3,4) or FKBP12. Our lead compounds display little or no activity in the dark but can be reversibly activated to varying degrees with different wavelengths of light. Our modular and generalizable approach provides a method for the optical control of protein levels with photopharmacology and could lead to new types of precision therapeutics that avoid undesired systemic toxicity.</i><b></b></p>

scholarly journals Long noncoding RNA SNHG14 promotes hepatocellular carcinoma progression by regulating miR-876-5p/SSR2 axis

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Zhibin Liao ◽  
Hongwei Zhang ◽  
Chen Su ◽  
Furong Liu ◽  
Yachong Liu ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Animal Experiments ◽  
Luciferase Reporter ◽  
Western Blot Assay ◽  
Downstream Target ◽  
Protein Levels ◽  
Elevated Expression ◽  
Rna Immunoprecipitation

Abstract Background Aberrant expressions of long noncoding RNAs (lncRNAs) have been demonstrated to be related to the progress of HCC. The mechanisms that SNHG14 has participated in the development of HCC are obscure. Methods Quantitative real-time PCR (qRT-PCR) was used to measure the lncRNA, microRNA and mRNA expression level. Cell migration, invasion and proliferation ability were evaluated by transwell and CCK8 assays. The ceRNA regulatory mechanism of SNHG14 was evaluated by RNA immunoprecipitation (RIP) and dual luciferase reporter assay. Tumorigenesis mouse model was used to explore the roles of miR-876-5p in vivo. The protein levels of SSR2 were measured by western blot assay. Results In this study, we demonstrated that SNHG14 was highly expressed in HCC tissues, meanwhile, the elevated expression of SNHG14 predicted poor prognosis in patients with HCC. SNHG14 promoted proliferation and metastasis of HCC cells. We further revealed that SNHG14 functioned as a competing endogenous RNA (ceRNA) for miR-876-5p and that SSR2 was a downstream target of miR-876-5p in HCC. Transwell, CCK8 and animal experiments exhibited miR-876-5p inhibited HCC progression in vitro and in vivo. By conducting rescue experiments, we found the overexpression of SSR2 or knocking down the level of miR-876-5p could reverse the suppressive roles of SNHG14 depletion in HCC. Conclusion SNHG14 promotes HCC progress by acting as a sponge of miR-876-5p to regulate the expression of SSR2 in HCC.

scholarly journals Effect of long-term refeeding on protein metabolism in patients with cirrhosis of the liver

1997 ◽  
Vol 77 (2) ◽  
pp. 197-212 ◽  
Author(s):  
Jens Kondrup ◽  
Klaus Nielsen ◽  
Anders Juul
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Protein Degradation ◽  
Protein Metabolism ◽  
Cirrhosis Of The Liver ◽  
N Balance ◽  
Whole Body ◽  
Protein Requirement ◽  
Protein Utilization ◽  
Igf I

Patients with cirrhosis of the liver require an increased amount of protein to achieve N balance. However, the utilization of protein with increased protein intake, i.e. the slope from regression analysis of N balance v. intake, is highly efficient (Nielsen et al. 1995). In the present study, protein requirement and protein utilization were investigated further by measuring protein synthesis and degradation. In two separate studies, five or six patients with cirrhosis of the liver were refed on a balanced diet for an average of 2 or 4 weeks. Protein and energy intakes were doubled in both studies. Initial and final whole-body protein metabolism was measured in the fed state by primed continous [15N]glycine infusion. Refeeding caused a statistically significant increase of about 30% in protein synthesis in both studies while protein degradation was only slightly affected. The increase in protein synthesis was associated with significant increases in plasma concentrations of total amino acids (25%), leucine (58%), isoleucine (82%), valine (72%), proline (48%) and triiodothyronine (27%) while insulin, growth hormone, insulin-like growth factor (IGF)-I and IGF-binding protein-3 were not changed significantly. The results indicate that the efficient protein utilization is due to increased protein synthesis, rather than decreased protein degradation, and suggest that increases in plasma amino acids may be responsible for the increased protein synthesis. A comparison of the patients who had a normal protein requirement with the patients who had an increased protein requirement suggests that the increased protein requirement is due to a primary increase in protein degradation. It is speculated that this is due to low levels of IGF-I secondary to impaired liver function, since initial plasma concentration of IGF-I was about 25% of control values and remained low during refeeding.

Mechanisms of renal tubular cell hypertrophy: mitogen-induced suppression of proteolysis

1997 ◽  
Vol 273 (3) ◽  
pp. C843-C851 ◽  
Author(s):  
H. A. Franch ◽  
P. V. Curtis ◽  
W. E. Mitch
Keyword(s):  
Protein Synthesis ◽  
Growth Factors ◽  
Growth Factor ◽  
Protein Degradation ◽  
Transforming Growth Factor ◽  
Primary Cultures ◽  
Renal Tubular Cell ◽  
Kidney Cells ◽  
Tgf Beta ◽  
Lysosomal Proteolysis

The combination of epidermal growth factor (EGF) plus transforming growth factor-beta 1 (TGF-beta 1) causes hypertrophy in renal epithelial cells. One mechanism contributing to hypertrophy is that EGF induces activation of the cell cycle and increases protein synthesis, whereas TGF-beta 1 prevents cell division, thereby converting hyperplasia to hypertrophy. To assess whether suppression of proteolysis is another mechanism causing hypertrophy induced by these growth factors, we measured protein degradation in primary cultures of proximal tubule cells and in cultured NRK-52E kidney cells. A concentration of 10(-8) M EGF alone or EGF plus 10(-10) M TGF-beta 1 decreased proteolysis by approximately 30%. TGF-beta 1 alone did not change protein degradation. Using inhibitors, we examined which proteolytic pathway is suppressed. Neither proteasome nor calpain inhibitors prevented the antiproteolytic response to EGF + TGF-beta 1. Inhibitors of lysosomal proteases eliminated the antiproteolytic response to EGF + TGF-beta 1, suggesting that these growth factors act to suppress lysosomal proteolysis. This antiproteolytic response was not caused by impaired EGF receptor signaling, since lysosomal inhibitors did not block EGF-induced protein synthesis. We conclude that suppression of lysosomal proteolysis contributes to growth factor-mediated hypertrophy of cultured kidney cells.

scholarly journals Changes of Nitrogen Compounds During Ensiling of High Protein Herbages – A Review

2015 ◽  
Vol 15 (2) ◽  
pp. 289-305 ◽  
Author(s):  
Maja Fijałkowska ◽  
Barbara Pysera ◽  
Krzysztof Lipiński ◽  
Danuta Strusińska
Keyword(s):  
Protein Synthesis ◽  
Protein Degradation ◽  
Crude Protein ◽  
Raw Material ◽  
Nitrogen Compounds ◽  
Microbial Protein ◽  
Fermentation Inhibitors ◽  
Protein Nitrogen ◽  
Microbial Protein Synthesis ◽  
Positive Effects

Abstract Losses of crude protein during ensiling of herbages, in contrast to carbohydrates, do not affect the reduction of its content; their form is changed into greater solubility non-protein compounds and also highly degraded forms, which lower the efficiency of the microbial protein synthesis in the rumen. These processes are accompanied by a change of amino acid composition of herbage protein and decrease in intestinal digestibility of protein from feeds as a result of the formation of indigestible complexes with carbohydrates (ADIN). Reduction of protein degradation in silages is achieved by accelerated acidity through addition of acids or dominance of homofermentative bacteria. The positive effects of fermentation inhibitors or sorbents use, as well as the wilting of raw material on the level and rate of protein degradation were demonstrated by many researchers. A greater contribution of protein nitrogen and reduction of deamination in silages can also be obtained by using bacteria inoculants. Increasing the proportion of protein nitrogen is accompanied by the improved efficiency of microbial protein synthesis.

Phased Protein Synthesis at Several Circadian Times Does Not Change Protein Levels in Gonyaulax

1996 ◽  
Vol 11 (1) ◽  
pp. 57-67 ◽  
Author(s):  
Paul Markovic ◽  
Till Roenneberg ◽  
David Morse
Keyword(s):  
Protein Synthesis ◽  
Protein Levels

Leucine metabolism in lactating and dry goats: effect of insulin and substrate availability

1993 ◽  
Vol 265 (3) ◽  
pp. E402-E413 ◽  
Author(s):  
S. Tesseraud ◽  
J. Grizard ◽  
E. Debras ◽  
I. Papet ◽  
Y. Bonnet ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Amino Acid ◽  
Protein Degradation ◽  
Whole Body ◽  
Initial Slope ◽  
Sensitivity Index ◽  
Early Lactation ◽  
Dry Period ◽  
Body Protein ◽  
Lactating Goats

Early lactating goats show insulin resistance with respect to extramammary glucose utilization. However, much less is known about the two major factors, insulin and plasma amino acid concentration, that regulate protein metabolism in lactating goats. To examine this question, the in vivo effect of acute insulin was studied in goats during early lactation (12-31 days postpartum), midlactation (98-143 days postpartum), and the dry period (approximately 1 yr postpartum). Insulin was infused (at 0.36 or 1.79 nmol/min) under euglycemic and eukaliemic clamps. In addition, appropriate amino acid infusion was used to blunt insulin-induced hypoaminoacidemia or to create hyperaminoacidemia and maintain this condition under insulin treatment. Leucine kinetics were assessed using a primed continuous infusion of L-[1-14C]-leucine, which started 2.5 h before insulin. In all animals the insulin treatments failed to stimulate the nonoxidative leucine disposal (an estimate of whole body protein synthesis) under both euaminoacidemic and hyperaminoacidemic conditions. Thus, in goat as well as humans, infusion of insulin fails to stimulate protein synthesis even when combined with a substantially increased provision of amino acids. In contrast, insulin treatments caused a dose-dependent inhibition of the endogenous leucine appearance (an estimate of whole body protein degradation). Under euaminoacidemia the initial slope from the plot of the endogenous leucine appearance as a function of plasma insulin (an insulin sensitivity index) was steeper during early lactation than when compared with the dry period. A similar trend occurred during midlactation but not to any significant degree. These differences were abolished under hyperaminoacidemia. It was concluded that the ability of physiological insulin to inhibit protein degradation was improved during lactation, demonstrating a clear-cut dissociation between the effects of insulin on protein and glucose metabolism. This adaptation no doubt may provide a mechanism to save body protein.

Effect of glutamine-enriched total parenteral nutrition on septic rats

1991 ◽  
Vol 81 (2) ◽  
pp. 215-222 ◽  
Author(s):  
M. Salleh M. Ardawi
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Parenteral Nutrition ◽  
Protein Degradation ◽  
Total Parenteral Nutrition ◽  
Nitrogen Balance ◽  
Cumulative Percentage ◽  
Better Than

1. The effect of total parenteral nutrition with or without glutamine enrichment was studied in septic rats after 4 days of treatment. 2. Septic rats treated with glutamine-enriched total parenteral nutrition survived sepsis significantly better than other TPN-treated septic rats: the cumulative percentage of deaths over 4 days in septic rats treated with glutamine-enriched total parenteral nutrition was 25% compared with 55% in septic rats given total parenteral nutrition without glutamine and 70% in septic rats given glucose. 3. Glutamine-enriched total parenteral nutrition resulted in improved nitrogen balance in septic rats: the cumulative nitrogen balance over the 4 days of treatment was the least negative as compared with other groups of septic rats. 4. The rate of loss of intracellular glutamine in skeletal muscle was markedly decreased (P < 0.001) in response to glutamine-enriched total parenteral nutrition in septic rats. 5. The rate of protein synthesis was increased (21.2%) and the rate of protein degradation was decreased (35.5%) in response to glutamine-enriched total parenteral nutrition in septic rats. 6. It is concluded that the administration of glutamine-enriched total parenteral nutrition is beneficial to septic rats and possibly to septic patients.

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