scholarly journals Widespread remodelling of proteome solubility in response to different protein homeostasis stresses

2019 ◽  
Author(s):  
Xiaojing Sui ◽  
Douglas E. V. Pires ◽  
Shuai Nie ◽  
Giulia Vecchi ◽  
Michele Vendruscolo ◽  
...  
Keyword(s):  
Protein Complexes ◽  
Protein Solubility ◽  
Specific Pattern ◽  
Regulatory Mechanisms ◽  
Protein Homeostasis ◽  
Neuro2a Cell ◽  
Aggregation State ◽  
Protein Deposits ◽  
Almost All ◽  
And Oxidative Stress

ABSTRACTThe accumulation of protein deposits in neurodegenerative diseases involves the presence of a metastable subproteome vulnerable to aggregation. To investigate this subproteome and the mechanisms that regulates it, we measured the proteome solubility of the Neuro2a cell line under protein homeostasis stresses induced by Huntington Disease proteotoxicity; Hsp70, Hsp90, proteasome and ER-mediated folding inhibition; and oxidative stress. We found one-quarter of the proteome extensively changed solubility. Remarkably, almost all the increases in insolubility were counteracted by increases in solubility of other proteins. Each stress directed a highly specific pattern of change, which reflected the remodelling of protein complexes involved in adaptation to perturbation, most notably stress granule proteins, which responded differently to different stresses. These results indicate that the robustness of protein homeostasis relies on the absence of proteins highly vulnerable to aggregation and on large changes in aggregation state of regulatory mechanisms that restore protein solubility upon specific perturbations.

scholarly journals Widespread remodeling of proteome solubility in response to different protein homeostasis stresses

2020 ◽  
Vol 117 (5) ◽  
pp. 2422-2431 ◽  
Author(s):  
Xiaojing Sui ◽  
Douglas E. V. Pires ◽  
Angelique R. Ormsby ◽  
Dezerae Cox ◽  
Shuai Nie ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Protein Complexes ◽  
Specific Pattern ◽  
Protein Homeostasis ◽  
Cellular Mechanisms ◽  
Neuro2a Cell ◽  
Protein Deposits ◽  
Almost All

The accumulation of protein deposits in neurodegenerative diseases has been hypothesized to depend on a metastable subproteome vulnerable to aggregation. To investigate this phenomenon and the mechanisms that regulate it, we measured the solubility of the proteome in the mouse Neuro2a cell line under six different protein homeostasis stresses: 1) Huntington’s disease proteotoxicity, 2) Hsp70, 3) Hsp90, 4) proteasome, 5) endoplasmic reticulum (ER)-mediated folding inhibition, and 6) oxidative stress. Overall, we found that about one-fifth of the proteome changed solubility with almost all of the increases in insolubility were counteracted by increases in solubility of other proteins. Each stress directed a highly specific pattern of change, which reflected the remodeling of protein complexes involved in adaptation to perturbation, most notably, stress granule (SG) proteins, which responded differently to different stresses. These results indicate that the protein homeostasis system is organized in a modular manner and aggregation patterns were not correlated with protein folding stability (ΔG). Instead, distinct cellular mechanisms regulate assembly patterns of multiple classes of protein complexes under different stress conditions.

scholarly journals Expression of the genes for the ferritin H and L subunits in rat liver and heart. Evidence for tissue-specific regulations at pre- and post-translational levels

1991 ◽  
Vol 275 (3) ◽  
pp. 813-816 ◽  
Author(s):  
G Cairo ◽  
E Rappocciolo ◽  
L Tacchini ◽  
L Schiaffonati
Keyword(s):  
Translational Regulation ◽  
Specific Pattern ◽  
Regulatory Mechanisms ◽  
Mrna Accumulation ◽  
Tissue Specific ◽  
Protein Levels ◽  
Ferritin Gene ◽  
Ferritin H ◽  
Translational Mechanisms ◽  
Different Tissues

The proportion of ferritin light-chain and heavy-chain subunits (L and H) present in the ferritin multimeric shell varies between different tissues. To identify the regulatory mechanisms responsible for the greater amount of L in liver than in heart isoferritins, we analysed ferritin-gene expression at the RNA and protein levels in these two tissues of the rat. In the heart the ratio between the amount of L and H, at the level both of synthesis and accumulation, is about 1 and is the same as the ratio between their respective mRNAs. In contrast, in the liver, the ratio between the L- and H-mRNAs is approx. 2 and cannot entirely explain the large predominance of L in isoferritins in this tissue. Since in the liver the L-mRNA is neither preferentially associated with polyribosomes nor translated more efficiently than its H- counterpart, it seems that the liver-specific isoferritin profile is determined by a combination of pre- and post-translational mechanisms, whereas in heart the post-translational regulation does not seem to be relevant and the tissue-specific pattern is determined at the level of mRNA accumulation.

scholarly journals Transcription Factors and microRNA Genes Regulatory Network Construction Under Drought Stress in Sesame (Sesamum indicum L.)

2020 ◽  
Author(s):  
Mohammad Amin Baghery ◽  
Seyed Kamal Kazemitabar ◽  
Ali Dehestani ◽  
Pooyan Mehrabanjoubani ◽  
Mohammad Mehdi Naghizadeh ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Drought Stress ◽  
Gene Networks ◽  
Regulatory Networks ◽  
Regulatory Gene ◽  
Sesamum Indicum ◽  
Regulatory Mechanisms ◽  
Oilseed Crop ◽  
Sesame Genotypes ◽  
Almost All

Abstract Background: Drought is one of the most common environmental stresses affecting crops yield and quality. Sesame is an important oilseed crop that most likely faces drought during its growth due to growing in semi-arid and arid areas. Plants responses to drought controlled by regulatory mechanisms. Despite this importance, there is little information about Sesame regulatory mechanisms against drought stress. Results: 458 drought-related genes were identified using comprehensive RNA-seq data analysis of two susceptible and tolerant sesame genotypes under drought stress. These drought-responsive genes were included secondary metabolites biosynthesis-related Like F3H, sucrose biosynthesis-related like SUS2, transporters like SUC2, and protectives like LEA and HSP families. Interactions between identified genes and regulators including TFs and miRNAs were predicted using bioinformatics tools and related regulatory gene networks were constructed. Key regulators and relations of Sesame under drought stress were detected by network analysis. TFs belonged to DREB (DREB2D), MYB (MYB63), ZFP (TFIIIA), bZIP (bZIP16), bHLH (PIF1), WRKY (WRKY30) and NAC (NAC29) families were found among key regulators. mRNAs like miR399, miR169, miR156, miR5685, miR529, miR395, miR396, and miR172 also found as key drought regulators. Furthermore, a total of 117 TFs and 133 miRNAs that might be involved in drought stress were identified with this approach. Conclusions: Most of the identified TFs and almost all of the miRNAs are introduced for the first time as potential regulators of drought response in Sesame. These regulators accompany with identified drought-related genes could be valuable candidates for future studies and breeding programs on Sesame under drought stress. Keywords: Sesamum indicum, Drought stress, Regulatory networks, miRNA, Transcription Factors.

scholarly journals The GTEx Consortium atlas of genetic regulatory effects across human tissues

Science ◽  
2020 ◽  
Vol 369 (6509) ◽  
pp. 1318-1330 ◽  
Author(s):  
Keyword(s):  
Complex Traits ◽  
Molecular Mechanisms ◽  
Tissue Expression ◽  
Genetic Effects ◽  
Regulatory Mechanisms ◽  
Human Tissues ◽  
Genetic Associations ◽  
Key Factor ◽  
Regulatory Effects ◽  
Almost All

The Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the version 8 data, examining 15,201 RNA-sequencing samples from 49 tissues of 838 postmortem donors. We comprehensively characterize genetic associations for gene expression and splicing in cis and trans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue specificity of genetic effects and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.

scholarly journals Pseudo-DUBs as allosteric activators and molecular scaffolds of protein complexes

2018 ◽  
Vol 46 (2) ◽  
pp. 453-466 ◽  
Author(s):  
Miriam Walden ◽  
Safi Kani Masandi ◽  
Krzysztof Pawłowski ◽  
Elton Zeqiraj
Keyword(s):  
Cell Biology ◽  
Protein Complexes ◽  
Cell Signalling ◽  
Control Cell ◽  
Mechanisms Of Action ◽  
Molecular Scaffolds ◽  
Polyubiquitin Chains ◽  
Macromolecular Complexes ◽  
Cellular Life ◽  
Almost All

The ubiquitin (Ub) proteasome system and Ub signalling networks are crucial to cell biology and disease development. Deubiquitylases (DUBs) control cell signalling by removing mono-Ub and polyubiquitin chains from substrates. DUBs take part in almost all processes that regulate cellular life and are frequently dysregulated in disease. We have catalogued 99 currently known DUBs in the human genome and sequence conservation analyses of catalytic residues suggest that 11 lack enzyme activity and are classed as pseudo-DUBs. These pseudoenzymes play important biological roles by allosterically activating catalytically competent DUBs as well as other active enzymes. Additionally, pseudoenzymes act as assembly scaffolds of macromolecular complexes. We discuss how pseudo-DUBs have lost their catalytic activity, their diverse mechanisms of action and their potential as therapeutic targets. Many known pseudo-DUBs play crucial roles in cell biology and it is likely that unstudied and overlooked pseudo-DUB genes will have equally important functions.

scholarly journals Transcriptome Analysis Reveals IsiA-Regulatory Mechanisms Underlying Iron Depletion and Oxidative-Stress Acclimation in Synechocystis sp. Strain PCC 6803

2020 ◽  
Vol 86 (13) ◽  
Author(s):  
Yarui Cheng ◽  
Tianyuan Zhang ◽  
Li Wang ◽  
Wenli Chen
Keyword(s):  
Oxidative Stress ◽  
Network Analysis ◽  
Iron Deficiency ◽  
Regulatory Mechanisms ◽  
Functional Modules ◽  
Iron Stress ◽  
Iron Starvation ◽  
Stress Acclimation ◽  
And Oxidative Stress ◽  
Coexpression Network Analysis

ABSTRACT Microorganisms in nature are commonly exposed to various stresses in parallel. The isiA gene encodes an iron stress-induced chlorophyll-binding protein which is significantly induced under iron starvation and oxidative stress. Acclimation of oxidative stress and iron deficiency was investigated using a regulatory mutant of the Synechocystis sp. strain PCC 6803. In this study, the ΔisiA mutant grew more slowly in oxidative-stress and iron depletion conditions compared to the wild-type (WT) counterpart under the same conditions. Thus, we performed transcriptome sequencing (RNA-seq) analysis of the WT strain and the ΔisiA mutant under double-stress conditions to obtain a comprehensive view of isiA-regulated genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed significant differences between the WT strain and ΔisiA mutant, mainly related to photosynthesis and the iron-sulfur cluster. The deletion of isiA affects the expression of various genes that are involved in cellular processes and structures, such as photosynthesis, phycobilisome, and the proton-transporting ATPase complex. Weighted gene coexpression network analysis (WGCNA) demonstrated three functional modules in which the turquoise module was negatively correlated with superoxide dismutase (SOD) activity. Coexpression network analysis identified several hub genes of each module. Cotranscriptional PCR and reads coverage using the Integrative Genomics Viewer demonstrated that isiA, isiB, isiC, ssl0461, and dfp belonged to the isi operon. Three sRNAs related to oxidative stress were identified. This study enriches our knowledge of IsiA-regulatory mechanisms under iron deficiency and oxidative stress. IMPORTANCE This study analyzed the impact of isiA deletion on the transcriptomic profile of Synechocystis. The isiA gene encodes an iron stress-induced chlorophyll-binding protein, which is significantly induced under iron starvation. The deletion of isiA affects the expression of various genes that are involved in photosynthesis and ABC transporters. WGCNA revealed three functional modules in which the blue module was correlated with oxidative stress. We further demonstrated that the isi operon contained the following five genes: isiA, isiB, isiC, ssl0461, and dfp by cotranscriptional PCR. Three sRNAs were identified that were related to oxidative stress. This study enhances our knowledge of IsiA-regulatory mechanisms under iron deficiency and oxidative stress.

scholarly journals The GTEx Consortium atlas of genetic regulatory effects across human tissues

2019 ◽  
Author(s):  
François Aguet ◽  
Alvaro N Barbeira ◽  
Rodrigo Bonazzola ◽  
Andrew Brown ◽  
Stephane E Castel ◽  
...  
Keyword(s):  
Complex Traits ◽  
Molecular Mechanisms ◽  
Tissue Expression ◽  
Genetic Effects ◽  
Regulatory Mechanisms ◽  
Human Tissues ◽  
Genetic Associations ◽  
Key Factor ◽  
Regulatory Effects ◽  
Almost All

AbstractThe Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues, and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the v8 data, based on 17,382 RNA-sequencing samples from 54 tissues of 948 post-mortem donors. We comprehensively characterize genetic associations for gene expression and splicing incisandtrans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue-specificity of genetic effects, and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.

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