scholarly journals Glucose intake hampers PKA-regulated HSP90 chaperone activity

2018 ◽  
Author(s):  
Yu-Chen Chen ◽  
Pei-Heng Jiang ◽  
Hsuan-Ming Chen ◽  
Chang-Han Chen ◽  
Yi-Ting Wang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Protein Quality ◽  
Glucose Sensing ◽  
Nutrient Sensing ◽  
Heat Sensitivity ◽  
Functional Screening ◽  
Quantitative Mass Spectrometry ◽  
Glucose Intake ◽  
Gradual Loss ◽  
Hsp90 Chaperone

AbstractAging is an intricate phenomenon associated with the gradual loss of physiological functions, and both nutrient sensing and proteostasis control lifespan. Although multiple approaches have facilitated the identification of candidate genes that govern longevity, the molecular mechanisms that link aging pathways are still elusive. Here, we conducted a quantitative mass spectrometry screen and identified all phosphorylation/dephosphorylation sites on yeast proteins that significantly responded to calorie restriction, a well-established approach to extend lifespan. Functional screening of 135 potential regulators uncovered that Ids2 is activated by PP2C under CR and inactivated by PKA under glucose intake. ids2Δ or ids2 phosphomimetic cells displayed heat sensitivity and lifespan shortening. Ids2 serves as a co-chaperone to form a complex with Hsc82 or the redundant Hsp82, and phosphorylation of Ids2 impedes its association with chaperone HSP90. Thus, PP2C and PKA orchestrate glucose sensing and protein folding to enable cells to maintain protein quality for sustained longevity.

scholarly journals Glucose intake hampers PKA-regulated HSP90 chaperone activity

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Yu-Chen Chen ◽  
Pei-Heng Jiang ◽  
Hsuan-Ming Chen ◽  
Chang-Han Chen ◽  
Yi-Ting Wang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Protein Quality ◽  
Glucose Sensing ◽  
Nutrient Sensing ◽  
Heat Sensitivity ◽  
Functional Screening ◽  
Quantitative Mass Spectrometry ◽  
Glucose Intake ◽  
Gradual Loss ◽  
Hsp90 Chaperone

Aging is an intricate phenomenon associated with the gradual loss of physiological functions, and both nutrient sensing and proteostasis control lifespan. Although multiple approaches have facilitated the identification of candidate genes that govern longevity, the molecular mechanisms that link aging pathways are still elusive. Here, we conducted a quantitative mass spectrometry screen and identified all phosphorylation/dephosphorylation sites on yeast proteins that significantly responded to calorie restriction, a well-established approach to extend lifespan. Functional screening of 135 potential regulators uncovered that Ids2 is activated by PP2C under CR and inactivated by PKA under glucose intake. ids2Δ or ids2 phosphomimetic cells displayed heat sensitivity and lifespan shortening. Ids2 serves as a co-chaperone to form a complex with Hsc82 or the redundant Hsp82, and phosphorylation impedes its association with chaperone HSP90. Thus, PP2C and PKA may orchestrate glucose sensing and protein folding to enable cells to maintain protein quality for sustained longevity.

scholarly journals Chemotherapy Resistance Explained through Endoplasmic Reticulum Stress-Dependent Signaling

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 338 ◽  
Author(s):  
Entaz Bahar ◽  
Ji-Ye Kim ◽  
Hyonok Yoon
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Molecular Mechanism ◽  
Molecular Mechanisms ◽  
Cellular Proliferation ◽  
Protein Quality ◽  
Chemotherapy Resistance ◽  
Persistent Problem ◽  
Stress Dependent ◽  
The Relationship

Cancers cells have the ability to develop chemotherapy resistance, which is a persistent problem during cancer treatment. Chemotherapy resistance develops through different molecular mechanisms, which lead to modification of the cancer cells signals needed for cellular proliferation or for stimulating an immune response. The endoplasmic reticulum (ER) is an important organelle involved in protein quality control, by promoting the correct folding of protein and ER-mediated degradation of unfolded or misfolded protein, namely, ER-associated degradation. Disturbances of the normal ER functions causes an accumulation of unfolded or misfolded proteins in the ER lumen, resulting in a condition called “ER stress (ERS).” ERS triggers the unfolded protein response (UPR)—also called the ERS response (ERSR)—to restore homeostasis or activate cell death. Although the ERSR is one emerging potential target for chemotherapeutics to treat cancer, it is also critical for chemotherapeutics resistance, as well. However, the detailed molecular mechanism of the relationship between the ERSR and tumor survival or drug resistance remains to be fully understood. In this review, we aim to describe the most vital molecular mechanism of the relationship between the ERSR and chemotherapy resistance. Moreover, the review also discusses the molecular mechanism of ER stress-mediated apoptosis on cancer treatments.

scholarly journals A Mep2-dependent Transcriptional Profile Links Permease Function to Gene Expression during Pseudohyphal Growth in Saccharomyces cerevisiae

2008 ◽  
Vol 19 (7) ◽  
pp. 3028-3039 ◽  
Author(s):  
Julian C. Rutherford ◽  
Gordon Chua ◽  
Timothy Hughes ◽  
Maria E. Cardenas ◽  
Joseph Heitman
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Map Kinase ◽  
Molecular Mechanisms ◽  
Nutrient Sensing ◽  
Transcriptional Profile ◽  
Regulatory Function ◽  
Pseudohyphal Growth ◽  
Epistasis Analysis ◽  
Map Kinase Pathway ◽  
Kinase Pathway

The ammonium permease Mep2 is required for the induction of pseudohyphal growth, a process in Saccharomyces cerevisiae that occurs in response to nutrient limitation. Mep2 has both a transport and a regulatory function, supporting models in which Mep2 acts as a sensor of ammonium availability. Potentially similar ammonium permease-dependent regulatory cascades operate in other fungi, and they may also function in animals via the homologous Rh proteins; however, little is known about the molecular mechanisms that mediate ammonium sensing. We show that Mep2 is localized to the cell surface during pseudohyphal growth, and it is required for both filamentous and invasive growth. Analysis of site-directed Mep2 mutants in residues lining the ammonia-conducting channel reveal separation of function alleles (transport and signaling defective; transport-proficient/signaling defective), indicating transport is necessary but not sufficient to sense ammonia. Furthermore, Mep2 overexpression enhances differentiation under normally repressive conditions and induces a transcriptional profile that is consistent with activation of the mitogen-activated protein (MAP) kinase pathway. This finding is supported by epistasis analysis establishing that the known role of the MAP kinase pathway in pseudohyphal growth is linked to Mep2 function. Together, these data strengthen the model that Mep2-like proteins are nutrient sensing transceptors that govern cellular differentiation.

scholarly journals Locked in a vicious cycle: the connection between genomic instability and a loss of protein homeostasis

2020 ◽  
Author(s):  
Wouter Huiting ◽  
Steven Bergink
Keyword(s):  
Control Systems ◽  
Genomic Instability ◽  
Therapeutic Strategy ◽  
Protein Quality ◽  
Accelerated Ageing ◽  
Protein Homeostasis ◽  
Vicious Cycle ◽  
Proteotoxic Stress ◽  
Gradual Loss ◽  
Wide Range

AbstractCardiomyopathies, neuropathies, cancer and accelerated ageing are unequivocally distinct diseases, yet they also show overlapping pathological hallmarks, including a gradual loss of genomic integrity and proteotoxic stress. Recent lines of evidence suggest that this overlap could be the result of remarkably interconnected molecular cascades between nuclear genomic instability and a loss of protein homeostasis. In this review, we discuss these complex connections, as well as their possible impact on disease. We focus in particular on the inherent ability of a wide range of genomic alterations to challenge protein homeostasis. In doing so, we provide evidence suggesting that a loss of protein homeostasis could be a far more prevalent consequence of genomic instability than generally believed. In certain cases, such as aneuploidy, a loss of protein homeostasis appears to be a crucial mechanism for pathology, which indicates that enhancing protein quality control systems could be a promising therapeutic strategy in diseases associated with genomic instability.

scholarly journals miR-181b negatively regulates activation-induced cytidine deaminase in B cells

2008 ◽  
Vol 205 (10) ◽  
pp. 2199-2206 ◽  
Author(s):  
Virginia G. de Yébenes ◽  
Laura Belver ◽  
David G. Pisano ◽  
Susana González ◽  
Aranzazu Villasante ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Bystander Effect ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Fine Tuning ◽  
Functional Screening ◽  
Activation Induced Cytidine Deaminase ◽  
Activated B Cells

Activated B cells reshape their primary antibody repertoire after antigen encounter by two molecular mechanisms: somatic hypermutation (SHM) and class switch recombination (CSR). SHM and CSR are initiated by activation-induced cytidine deaminase (AID) through the deamination of cytosine residues on the immunoglobulin loci, which leads to the generation of DNA mutations or double-strand break intermediates. As a bystander effect, endogenous AID levels can also promote the generation of chromosome translocations, suggesting that the fine tuning of AID expression may be critical to restrict B cell lymphomagenesis. To determine whether microRNAs (miRNAs) play a role in the regulation of AID expression, we performed a functional screening of an miRNA library and identified miRNAs that regulate CSR. One such miRNA, miR-181b, impairs CSR when expressed in activated B cells, and results in the down-regulation of AID mRNA and protein levels. We found that the AID 3′ untranslated region contains multiple putative binding sequences for miR-181b and that these sequences can be directly targeted by miR-181b. Overall, our results provide evidence for a new regulatory mechanism that restricts AID activity and can therefore be relevant to prevent B cell malignant transformation.

scholarly journals Resveratrol Attenuates Copper-Induced Senescence by Improving Cellular Proteostasis

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Liliana Matos ◽  
Alexandra Monteiro Gouveia ◽  
Henrique Almeida
Keyword(s):  
Molecular Mechanisms ◽  
Protein Quality ◽  
Replicative Senescence ◽  
Beneficial Effects ◽  
Cell Dysfunction ◽  
Age Related ◽  
Cell Tissue ◽  
Autophagy Induction ◽  
Human Disorders ◽  
Senescence Associated Genes

Copper sulfate-induced premature senescence (CuSO4-SIPS) consistently mimetized molecular mechanisms of replicative senescence, particularly at the endoplasmic reticulum proteostasis level. In fact, disruption of protein homeostasis has been associated to age-related cell/tissue dysfunction and human disorders susceptibility. Resveratrol is a polyphenolic compound with proved antiaging properties under particular conditions. In this setting, we aimed to evaluate resveratrol ability to attenuate cellular senescence induction and to unravel related molecular mechanisms. Using CuSO4-SIPS WI-38 fibroblasts, resveratrol is shown to attenuate typical senescence alterations on cell morphology, senescence-associated beta-galactosidase activity, and cell proliferation. The mechanisms implicated in this antisenescence effect seem to be independent of senescence-associated genes and proteins regulation but are reliant on cellular proteostasis improvement. In fact, resveratrol supplementation restores copper-induced increased protein content, attenuates BiP level, and reduces carbonylated and polyubiquitinated proteins by autophagy induction. Our data provide compelling evidence for the beneficial effects of resveratrol by mitigating CuSO4-SIPS stressful consequences by the modulation of protein quality control systems. These findings highlight the importance of a balanced cellular proteostasis and add further knowledge on molecular mechanisms mediating resveratrol antisenescence effects. Moreover, they contribute to identifying specific molecular targets whose modulation will prevent age-associated cell dysfunction and improve human healthspan.

scholarly journals Comprehensive functional screening of miRNAs involved in fat cell insulin sensitivity among women

2017 ◽  
Vol 312 (6) ◽  
pp. E482-E494 ◽  
Author(s):  
Ingrid Dahlman ◽  
Yasmina Belarbi ◽  
Jurga Laurencikiene ◽  
Annie M. Pettersson ◽  
Peter Arner ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Differential Expression ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Functional Screening ◽  
Fat Cell ◽  
Subcutaneous White Adipose Tissue ◽  
Micro Rnas

The key pathological link between obesity and type 2 diabetes is insulin resistance, but the molecular mechanisms are not entirely identified. micro-RNAs (miRNA) are dysregulated in obesity and may contribute to insulin resistance. Our objective was to detect and functionally investigate miRNAs linked to insulin sensitivity in human subcutaneous white adipose tissue (scWAT). Subjects were selected based on the insulin-stimulated lipogenesis response of subcutaneous adipocytes. Global miRNA profiling was performed in abdominal scWAT of 18 obese insulin-resistance (OIR), 21 obese insulin-sensitive (OIS), and 9 lean women. miRNAs demonstrating differential expression between OIR and OIS women were overexpressed in human in vitro-differentiated adipocytes followed by assessment of lipogenesis and identification of miRNA targets by measuring mRNA/protein expression and 3′-untranslated region analysis. Eleven miRNAs displayed differential expression between OIR and OIS states. Overexpression of miR-143-3p and miR-652-3p increased insulin-stimulated lipogenesis in human in vitro differentiated adipocytes and directly or indirectly affected several genes/proteins involved in insulin signaling at transcriptional or posttranscriptional levels. Adipose expression of miR-143-3p and miR-652-3p was positively associated with insulin-stimulated lipogenesis in scWAT independent of body mass index. In conclusion, miR-143-3p and miR-652-3p are linked to scWAT insulin resistance independent of obesity and influence insulin-stimulated lipogenesis by interacting at different steps with insulin-signaling pathways.

scholarly journals Salvage NAD+ Biosynthetic Pathway Enzymes Moonlight as Molecular Chaperones to Protect Against Proteotoxicity

2020 ◽  
Author(s):  
Meredith Pinkerton ◽  
Andrea Ruetenik ◽  
Viktoriia Bazylianska ◽  
Eva Nyvltova ◽  
Antoni Barrientos
Keyword(s):  
Control Systems ◽  
Molecular Chaperones ◽  
Biosynthetic Pathway ◽  
Protein Quality ◽  
Cellular Protein ◽  
Salvage Pathway ◽  
Abnormal Protein ◽  
Proteotoxic Stress ◽  
Evolutionarily Conserved ◽  
Hsp90 Chaperone

AbstractHuman neurodegenerative proteinopathies are disorders associated with abnormal protein depositions in brain neurons. They include polyglutamine (polyQ) conditions such as Huntington’s disease (HD) and α-synucleinopathies such as Parkinson’s disease (PD). Overexpression of NMNAT/Nma1, an enzyme in the NAD+ biosynthetic salvage pathway, acts as an efficient suppressor of proteotoxicities in yeast, fly, and mouse models. Screens in yeast models of HD and PD allowed us to identify three additional enzymes of the same pathway that achieve similar protection against proteotoxic stress: Npt1, Pnc1, and Qns1. Here, we report that their ability to maintain proteostasis is independent of their catalytic activity and does not require cellular protein quality control systems such as the proteasome or autophagy. Furthermore, we show that, under proteotoxic stress, the four proteins are recruited as molecular chaperones with holdase and foldase activities. The NAD+ salvage proteins act by preventing misfolding and, together with the Hsp90 chaperone, promoting the refolding of extended polyQ domains or α-synuclein. We conclude that the entire salvage NAD+ biosynthetic pathway links NAD+ metabolism and proteostasis and emerges as a target for therapeutics to combat age-associated neurodegenerative proteotoxicities. Our observations also illustrate the existence of an evolutionarily conserved strategy of repurposing or moonlighting housekeeping enzymes under stress conditions to maintain proteostasis.

scholarly journals Genome-wide transcript and protein analysis reveals distinct features of aging in the mouse heart

2020 ◽  
Author(s):  
Isabela Gerdes Gyuricza ◽  
Joel M. Chick ◽  
Gregory R. Keele ◽  
Andrew G. Deighan ◽  
Steven C. Munger ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Protein Quality ◽  
Expression Patterns ◽  
Genetic Regulation ◽  
Natural Aging ◽  
Endoplasmic Reticulum Stress Response ◽  
Mouse Heart ◽  
Matrix Remodeling ◽  
Age Related ◽  
Outbred Mice

ABSTRACTUnderstanding the molecular mechanisms underlying age-related changes in the heart is challenging due to the contributions from numerous genetic and environmental factors. Genetically diverse outbred mice provide a model to study the genetic regulation of aging processes in healthy tissues from individuals undergoing natural aging in a controlled environment. We analyzed transcriptome and proteome data from outbred mice at 6, 12 and 18 months of age to reveal a scenario of cardiac hypertrophy, fibrosis, extracellular matrix remodeling, and reemergence of fetal gene expression patterns. We observed widespread changes in protein trafficking and sorting, and post-translational disruption of the stoichiometry of the protein quality control system itself. We identified genome hotspots of age-by-genetic effects that regulate proteins from the proteasome and endoplasmic reticulum stress response, suggesting that genetic variation in these modules may contribute to individual variation in the aging heart.

scholarly journals Sex-specific transcriptomic responses to changes in the nutritional environment

2019 ◽  
Author(s):  
M. Florencia Camus ◽  
Matthew D.W. Piper ◽  
Max Reuter
Keyword(s):  
Molecular Mechanisms ◽  
Nutrient Sensing ◽  
Male And Female ◽  
Reproductive Genes ◽  
Metabolic Genes ◽  
Nutritional Environment ◽  
Males And Females ◽  
Dietary Variation ◽  
Protein Rich ◽  
Female Responses

AbstractMales and females typically pursue divergent reproductive strategies and accordingly require different dietary compositions to maximise their fitness. Here we move from identifying sex-specific optimal diets to understanding the molecular mechanisms that underlie male and female responses to dietary variation. We examine male and female gene expression on male-optimal (carbohydrate-rich) and female-optimal (protein-rich) diets. We find that the sexes share a large core of metabolic genes that are concordantly regulated in response to dietary composition. However, we also observe smaller sets of genes with divergent and opposing regulation, most notably in reproductive genes which are over-expressed on each sex’s optimal diet. Our results suggest that nutrient sensing output emanating from a shared metabolic machinery are reversed in males and females, leading to opposing diet-dependent regulation of reproduction in males and females. Further analysis and experiments suggest that this reverse regulation occurs within the IIS/TOR network.

Sign in / Sign up

Export Citation Format

Share Document