scholarly journals Ncl1 mediated metabolic rewiring critical during metabolic stress

2019 ◽  
Author(s):  
Ajay Bhat ◽  
Rahul Chakraborty ◽  
Khushboo Adlakha ◽  
Ganesh Agam ◽  
Kausik Chakraborty ◽  
...  
Keyword(s):  
Amino Acid ◽  
Translational Control ◽  
Metabolic Stress ◽  
Tca Cycle ◽  
Protein Translation ◽  
Leucine Supplementation ◽  
Nutritional Limitation ◽  
Trna Methyltransferase ◽  
Amino Acid Levels

AbstractNutritional limitation has been vastly studied, however, there is limited knowledge of how cells maintain homeostasis in excess nutrients. In this study, using yeast as a model system, we show that some amino acids are toxic at higher concentrations. With cysteine as a physiologically relevant example, we delineated the pathways/processes that are altered and those that are involved in survival in presence of elevated levels of this amino acid. Using proteomics and metabolomics approach, we found that cysteine upregulates proteins involved in amino acid metabolism, alters amino acid levels, and inhibits protein translation, events that are rescued by leucine supplementation. Through a comprehensive genetic screen we show that leucine mediated effect depends on a tRNA methyltransferase (Ncl1), absence of which decouples cell’s transcription and translation, inhibits the conversation of leucine to ketoisocaproate and leads to TCA cycle block. We therefore, propose a role of Ncl1 in regulating metabolic homeostasis through translational control.

scholarly journals Ncl1-mediated metabolic rewiring critical during metabolic stress

2019 ◽  
Vol 2 (4) ◽  
pp. e201900360 ◽  
Author(s):  
Ajay Bhat ◽  
Rahul Chakraborty ◽  
Khushboo Adlakha ◽  
Ganesh Agam ◽  
Kausik Chakraborty ◽  
...  
Keyword(s):  
Amino Acid ◽  
Translational Control ◽  
Acid Metabolism ◽  
Tricarboxylic Acid Cycle ◽  
Metabolic Stress ◽  
Protein Translation ◽  
Leucine Supplementation ◽  
Nutritional Limitation ◽  
Amino Acid Levels

Nutritional limitation has been vastly studied; however, there is limited knowledge of how cells maintain homeostasis in excess nutrients. In this study, using yeast as a model system, we show that some amino acids are toxic at higher concentrations. With cysteine as a physiologically relevant example, we delineated the pathways/processes that are altered and those that are involved in survival in the presence of elevated levels of this amino acid. Using proteomics and metabolomics approach, we found that cysteine up-regulates proteins involved in amino acid metabolism, alters amino acid levels, and inhibits protein translation—events that are rescued by leucine supplementation. Through a comprehensive genetic screen, we show that leucine-mediated effect depends on a transfer RNA methyltransferase (NCL1), absence of which decouples transcription and translation in the cell, inhibits the conversion of leucine to ketoisocaproate, and leads to tricarboxylic acid cycle block. We therefore propose a role of NCL1 in regulating metabolic homeostasis through translational control.

scholarly journals Amino Acids Promote Mitochondrial-Derived Compartment Formation in Mammalian Cells

2020 ◽  
Author(s):  
Max-Hinderk Schuler ◽  
Alyssa M. English ◽  
Leah VanderMeer ◽  
Janet M. Shaw ◽  
Adam L. Hughes
Keyword(s):  
Amino Acid ◽  
Mammalian Cells ◽  
Metabolic Stress ◽  
Amino Acid Content ◽  
Protein Translation ◽  
Translation Inhibition ◽  
Evolutionarily Conserved ◽  
Amino Acid Levels ◽  
Mitochondrial Remodeling ◽  
Cellular Stressors

SUMMARYWe recently identified a new cellular structure in yeast, called the Mitochondrial-Derived Compartment (MDC), that forms on mitochondria in response to amino acid excess. While emerging evidence supports an important function for MDCs in protecting cells from metabolic stress, whether this system exists beyond yeast remains unclear. Here, we show that MDCs are conserved in mammals, and like their yeast counterparts, are responsive to the intracellular amino acid content. Specifically, we find that inhibition of protein translation stimulates formation of dynamic, micron-sized compartments that associate with the mitochondrial network. These compartments are enriched for the carrier receptor Tomm70A and other select mitochondrial outer and inner membrane cargo, associate with the ER membrane, and require the conserved GTPase Miro1 for formation. Mammalian MDCs are responsive to changes in amino acid levels during translation inhibition, and are not activated by other common cellular stressors. Thus, MDCs represent an evolutionarily conserved nutrient-responsive mitochondrial remodeling system.

scholarly journals Deubiquitinating enzyme USP30 maintains basal peroxisome abundance by regulating pexophagy

2019 ◽  
Vol 218 (3) ◽  
pp. 798-807 ◽  
Author(s):  
Victoria Riccio ◽  
Nicholas Demers ◽  
Rong Hua ◽  
Miluska Vissa ◽  
Derrick T. Cheng ◽  
...  
Keyword(s):  
Amino Acid ◽  
Ubiquitin Ligase ◽  
Cell Function ◽  
E3 Ubiquitin Ligase ◽  
Metabolic Stress ◽  
Amino Acid Starvation ◽  
Deubiquitinating Enzyme ◽  
Potential Therapeutic Target ◽  
Autophagic Degradation

The regulation of organelle abundance is critical for cell function and survival; however, the mechanisms responsible are not fully understood. In this study, we characterize a role of the deubiquitinating enzyme USP30 in peroxisome maintenance. Peroxisomes are highly dynamic, changing in abundance in response to metabolic stress. In our recent study identifying the role of USP30 in mitophagy, we observed USP30 to be localized to punctate structures resembling peroxisomes. We report here that USP30, best known as a mitophagy regulator, is also necessary for regulating pexophagy, the selective autophagic degradation of peroxisomes. We find that overexpressing USP30 prevents pexophagy during amino acid starvation, and its depletion results in pexophagy induction under basal conditions. We demonstrate that USP30 prevents pexophagy by counteracting the action of the peroxisomal E3 ubiquitin ligase PEX2. Finally, we show that USP30 can rescue the peroxisome loss observed in some disease-causing peroxisome mutations, pointing to a potential therapeutic target.

C/EBPb Is a Critical Mediator of Resistance to IMiD® Immunomodulatory Compounds and Affected by IMiD Compounds Via Control of Protein Translation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 135-135
Author(s):  
Shirong Li ◽  
Rekha Pal ◽  
Sara Monaghan ◽  
Peter Schafer ◽  
Hongjiao Ouyang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Translational Control ◽  
Critical Role ◽  
Protein Translation ◽  
Thymidine Uptake ◽  
Double Labeling ◽  
Equity Ownership

Abstract Abstract 135 Background: Lenalidomide and pomalidomide are IMiD® immunomodulatory compounds that have been shown to be highly active in the treatment of multiple myeloma (MM). IMiD compounds exert their anti-tumor effects via acting on costimulatory proteins of T cells and NK cells, augmenting both the adaptive and innate immune system. But the mechanisms by which IMiD compounds directly inhibit MM cell proliferation are still unclear. Here we focused on the direct effects of IMiD compounds alone on MM cells. Results and Methods: We found that IMiDs, at concentrations as low as 0.01 μ M, induce significant inhibition of DNA synthesis in MM cells as shown by thymidine uptake. Since our previous work demonstrated that C/EBPβ is an important transcription factor which controls the growth and proliferation of myeloma cells, we analyzed the effects of IMiD compounds on C/EBPβ. We found that both pomalidomide and lenalidomide significantly decreased the protein level of C/EBPβ LAP-isoform in MM cell lines and primary MM cells. IMiD compound-induced suppression of C/EBPβ protein expression led to impaired transcription of the downstream IRF4, and subsequently to downregulation of BLIMP1 and XBP1, which are all critical for MM survival. To confirm our findings in vivo, we analyzed IRF4 expression by double labeling (IRF4+/CD138+) immunohistochemical staining of bone marrow biopsy samples of 23 myeloma patients prior to therapy and during therapy with lenalidomide. During lenalidomide therapy, the bone marrow MM cells showed a significantly weaker staining intensity for IRF4 in comparison to prior therapy. This was quantified by a significant (p<0.001) decrease of the staining score from 176 to 152, respectively. To confirm the critical role of C/EBPβ in MM we stably overexpressed C/EBPβ in MM cells. Overexpression of C/EBPβ prevented IMiD compound-induced inhibition of MM cell proliferation, indicating that C/EBPβ is critical in mediating resistance to IMiD compounds. This was supported by the fact that C/EBPβ was not down regulated in IMiD-resistant cell lines by IMiD treatment. Dissection of the C/EBPβ protein regulation revealed that IMiD compounds shut down C/EBPβ protein translation by decreasing eIF-4E. Knockdown experiments of eIF-4e resulted in downregulation of C/EBPβ, suggesting that C/EBPβ is under translational control in MM. Conclusions: Our studies, for the first time, provide evidence that IMiD compounds inhibit MM cell proliferation and survival by affecting the translation of C/EBPβ and subsequently multiple downstream transcription factors including IRF4, BLIMP1 and XBP1. Due to the critical role of C/EBPβ in mediating effects of IMiD compounds in MM, it might be a target to overcome drug resistance to IMiD compounds. The fact that pomalidomide can overcome resistance to lenalidomide in MM requires still further evaluation. Disclosures: Schafer: Celgene Corporation: Employment, Equity Ownership. Mapara:Gentium: Equity Ownership. Lentzsch:Celgene Corp: Research Funding.

scholarly journals In vivo vizualisation of mono-ADP-ribosylation by dPARP16 upon amino-acid starvation

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Angelica Aguilera-Gomez ◽  
Marinke M van Oorschot ◽  
Tineke Veenendaal ◽  
Catherine Rabouille
Keyword(s):  
Amino Acid ◽  
Metabolic Stress ◽  
Amino Acid Starvation ◽  
Critical Event ◽  
Post Translational Modification ◽  
Adp Ribosylation ◽  
Body Component ◽  
Necessary And Sufficient

PARP catalysed ADP-ribosylation is a post-translational modification involved in several physiological and pathological processes, including cellular stress. In order to visualise both Poly-, and Mono-, ADP-ribosylation in vivo, we engineered specific fluorescent probes. Using them, we show that amino-acid starvation triggers an unprecedented display of mono-ADP-ribosylation that governs the formation of Sec body, a recently identified stress assembly that forms in Drosophila cells. We show that dPARP16 catalytic activity is necessary and sufficient for both amino-acid starvation induced mono-ADP-ribosylation and subsequent Sec body formation and cell survival. Importantly, dPARP16 catalyses the modification of Sec16, a key Sec body component, and we show that it is a critical event for the formation of this stress assembly. Taken together our findings establish a novel example for the role of mono-ADP-ribosylation in the formation of stress assemblies, and link this modification to a metabolic stress.

scholarly journals Amino Acid Flux from Metabolic Network Benefits Protein Translation: the Role of Resource Availability

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Xiao-Pan Hu ◽  
Yi Yang ◽  
Bin-Guang Ma
Keyword(s):  
Amino Acid ◽  
Metabolic Network ◽  
Resource Availability ◽  
Protein Translation ◽  
Amino Acid Flux

scholarly journals Contribution of Energy Dysfunction to Impaired Protein Translation in Neurodegenerative Diseases

2021 ◽  
Vol 15 ◽  
Author(s):  
Yu-Ju Liu ◽  
Yijuang Chern
Keyword(s):  
Neurodegenerative Diseases ◽  
Translational Control ◽  
Energy Homeostasis ◽  
Protein Translation ◽  
Translational Machinery ◽  
Cellular Energy ◽  
Mechanistic Target Of Rapamycin ◽  
Translational Regulators ◽  
Lateral Sclerosis

Impaired energy homeostasis and aberrant translational control have independently been implicated in the pathogenesis of neurodegenerative diseases. AMP kinase (AMPK), regulated by the ratio of cellular AMP and ATP, is a major gatekeeper for cellular energy homeostasis. Abnormal regulation of AMPK has been reported in several neurodegenerative diseases, including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). Most importantly, AMPK activation is known to suppress the translational machinery by inhibiting the mechanistic target of rapamycin complex 1 (mTORC1), activating translational regulators, and phosphorylating nuclear transporter factors. In this review, we describe recent findings on the emerging role of protein translation impairment caused by energy dysregulation in neurodegenerative diseases.

Mechanism of Action of C2H4 in Promoting the Germination of Cocklebur Seeds. II. The Role of C2H4 in the Enhancement of Priming Effects

1996 ◽  
Vol 23 (2) ◽  
pp. 133 ◽  
Author(s):  
M Yoshiyama ◽  
H Yajima ◽  
T Atsumi ◽  
Y Esashi
Keyword(s):  
Water Stress ◽  
Amino Acid ◽  
Priming Effect ◽  
Seed Priming ◽  
Priming Effects ◽  
Acid Accumulation ◽  
Amino Acid Levels ◽  
Amino Acid Contents ◽  
Amino Acid Accumulation

In cocklebur (Xanthium pennsylvanicum Wallr.) seeds, the pre-exposure to water stress imposed by polyethylene glycol or mannitol (seed priming) increased osmotic pressure (OP) in cell saps and water extracts. Carbohydrates were the major components and soluble proteins also played a partial role as an osmoregulator in the primed seeds. C2H4, which was effective in stimulating the growth of both axial and cotyledonary tissues even under water-stressed conditions, changed the amino acid pool size regardless of water stress. This C2H4-induced amino acid accumulation also occurred under anoxic conditions. CO2 was capable of stimulating growth of axial tissues but it did not increase OP values or carbohydrate and amino acid contents. The effectiveness of seed primlng gradually declined with increasing duration of presoaking, but C2H4 prevented the reduction of the priming effect by effectively maintaining the amino acid levels. Thus, it is likely that C2H4 contributes to the enhancement of the priming effect by abundantly supplying amino acids.

scholarly journals Comparative proteomic analysis reveals the regulatory network of the veA gene during asexual and sexual spore development of Aspergillus cristatus

2018 ◽  
Vol 38 (4) ◽  
Author(s):  
Hui Liu ◽  
Shilei Sang ◽  
Hui Wang ◽  
Xiyi Ren ◽  
Yumei Tan ◽  
...  
Keyword(s):  
Amino Acid ◽  
Tca Cycle ◽  
Pentose Phosphate ◽  
2D Electrophoresis ◽  
Hypertonic Medium ◽  
Spore Development ◽  
Associated Proteins ◽  
Hsp 90 ◽  
Aspergillus Cristatus

Aspergillus cristatus is the predominant fungal population during fermentation of Chinese Fuzhuan brick tea, and belongs to the homothallic fungal group that undergoes a sexual stage without asexual conidiation under hypotonic conditions, while hypertonic medium induces initiation of the asexual stage and completely blocks sexual development. However, the veA deletion mutant only produces conidia in hypotonic medium after a 24-h culture, but both asexual and sexual spores are observed after 72 h. The veA gene is one of the key genes that positively regulates sexual and negatively regulates asexual development in A. cristatus. To elucidate the molecular mechanism of how VeA regulates asexual and sexual spore development in A. cristatus, 2D electrophoresis (2-DE) combined with MALDI-tandem ToF MS analysis were applied to identify 173 differentially expressed proteins (DEPs) by comparing the agamotype (24 h) and teleomorph (72 h) with wild-type (WT) A. cristatus strains. Further analysis revealed that the changed expression pattern of Pmk1-MAPK and Ser/Thr phosphatase signaling, heat shock protein (Hsp) 90 (HSP90), protein degradation associated, sulphur-containing amino acid biosynthesis associated, valine, leucine, isoleucine, and arginine biosynthesis involved, CYP450 and cytoskeletal formation associated proteins were involved in the production of conidia in agamotype of A. cristatus. Furthermore, the deletion of veA in A. cristatus resulted in disturbed process of transcription, translation, protein folding, amino acid metabolism, and secondary metabolism. The carbohydrate and energy metabolism were also greatly changed, which lied in the suppression of anabolism through pentose phosphate pathway (PPP) but promotion of catabolism through glycolysis and tricarboxylic acid (TCA) cycle. The energy compounds produced in the agamotype were mainly ATP and NADH, whereas they were NADPH and FAD in the teleomorph. These results will contribute to the existing knowledge on the complex role of VeA in the regulation of spore development in Aspergillus and provide a framework for functional investigations on the identified proteins.

scholarly journals Functional Amino Acids and Autophagy: Diverse Signal Transduction and Application

2021 ◽  
Vol 22 (21) ◽  
pp. 11427
Author(s):  
Chunchen Liu ◽  
Linbao Ji ◽  
Jinhua Hu ◽  
Ying Zhao ◽  
Lee J. Johnston ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Amino Acids ◽  
Amino Acid ◽  
Mammalian Target Of Rapamycin ◽  
Comprehensive Overview ◽  
Related Disease ◽  
Signal Relay ◽  
Amino Acid Levels ◽  
Amino Acid Sensing

Functional amino acids provide great potential for treating autophagy-related diseases by regulating autophagy. The purpose of the autophagy process is to remove unwanted cellular contents and to recycle nutrients, which is controlled by many factors. Disordered autophagy has been reported to be associated with various diseases, such as cancer, neurodegeneration, aging, and obesity. Autophagy cannot be directly controlled and dynamic amino acid levels are sufficient to regulate autophagy. To date, arginine, leucine, glutamine, and methionine are widely reported functional amino acids that regulate autophagy. As a signal relay station, mammalian target of rapamycin complex 1 (mTORC1) turns various amino acid signals into autophagy signaling pathways for functional amino acids. Deficiency or supplementation of functional amino acids can immediately regulate autophagy and is associated with autophagy-related disease. This review summarizes the mechanisms currently involved in autophagy and amino acid sensing, diverse signal transduction among functional amino acids and autophagy, and the therapeutic appeal of amino acids to autophagy-related diseases. We aim to provide a comprehensive overview of the mechanisms of amino acid regulation of autophagy and the role of functional amino acids in clinical autophagy-related diseases and to further convert these mechanisms into feasible therapeutic applications.

Sign in / Sign up

Export Citation Format

Share Document