scholarly journals Nα-terminal acetylation of proteins by NatA and NatB serves distinct physiological roles in Saccharomyces cerevisiae

2019 ◽  
Author(s):  
Ulrike A. Friedrich ◽  
Mostafa Zedan ◽  
Bernd Hessling ◽  
Kai Fenzl ◽  
Ludovic Gillet ◽  
...  
Keyword(s):  
Stress Responses ◽  
Ribosomal Proteins ◽  
Protein Modification ◽  
Protein Quality ◽  
Biological Significance ◽  
General Role ◽  
Altered Expression ◽  
Phenotypic Differences ◽  
Genes Encoding

SummaryN-terminal (Nt)-acetylation is a highly prevalent co-translational protein modification in eukaryotes, catalyzed by at least five Nt-acetyltransferases (Nat) with differing specificities. Nt-acetylation has been implicated in protein quality control but its broad biological significance remains elusive. We investigated the roles of the two major Nats of S. cerevisiae, NatA and NatB, by performing transcriptome, translatome and proteome profiling of natAΔ and natBΔ mutants. Our results do not support a general role of Nt-acetylation in protein degradation but reveal an unexpected range of Nat-specific phenotypes. NatA is implicated in systemic adaptation control, as natAΔ mutants display altered expression of transposons, sub-telomeric genes, pheromone response genes and nuclear genes encoding mitochondrial ribosomal proteins. NatB predominantly affects protein folding, as natBΔ mutants accumulate protein aggregates, induce stress responses and display reduced fitness in absence of the ribosome-associated chaperone Ssb. These phenotypic differences indicate that controlling Nat activities may serve to elicit distinct cellular responses.

scholarly journals Expanding Role of Ubiquitin in Translational Control

2020 ◽  
Vol 21 (3) ◽  
pp. 1151 ◽  
Author(s):  
Shannon E. Dougherty ◽  
Austin O. Maduka ◽  
Toshifumi Inada ◽  
Gustavo M. Silva
Keyword(s):  
Translational Control ◽  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Rna Binding ◽  
Protein Quality ◽  
Rna Binding Proteins ◽  
Ubiquitin Chain ◽  
Molecular Aspects ◽  
And Function

The eukaryotic proteome has to be precisely regulated at multiple levels of gene expression, from transcription, translation, and degradation of RNA and protein to adjust to several cellular conditions. Particularly at the translational level, regulation is controlled by a variety of RNA binding proteins, translation and associated factors, numerous enzymes, and by post-translational modifications (PTM). Ubiquitination, a prominent PTM discovered as the signal for protein degradation, has newly emerged as a modulator of protein synthesis by controlling several processes in translation. Advances in proteomics and cryo-electron microscopy have identified ubiquitin modifications of several ribosomal proteins and provided numerous insights on how this modification affects ribosome structure and function. The variety of pathways and functions of translation controlled by ubiquitin are determined by the various enzymes involved in ubiquitin conjugation and removal, by the ubiquitin chain type used, by the target sites of ubiquitination, and by the physiologic signals triggering its accumulation. Current research is now elucidating multiple ubiquitin-mediated mechanisms of translational control, including ribosome biogenesis, ribosome degradation, ribosome-associated protein quality control (RQC), and redox control of translation by ubiquitin (RTU). This review discusses the central role of ubiquitin in modulating the dynamism of the cellular proteome and explores the molecular aspects responsible for the expanding puzzle of ubiquitin signals and functions in translation.

Monozygotic Twins Display Different Minor Histocompatibility Antigens.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4324-4324
Author(s):  
Miroslaw Markiewicz ◽  
Urszula Siekiera ◽  
Monika Dzierzak Mietla ◽  
Agnieszka Karolczyk ◽  
Tomasz Kruzel ◽  
...  
Keyword(s):  
Large Scale ◽  
Hematological Malignancies ◽  
Conflicts Of Interest ◽  
Monozygotic Twins ◽  
Genotypic Diversity ◽  
Histocompatibility Antigens ◽  
Phenotypic Differences ◽  
Minor Histocompatibility Antigens ◽  
Genes Encoding

Abstract Abstract 4324 Introduction Albeit it is generally presumed that monozygotic twins are genetically identical and that phenotypic differences between twins are mainly due to environmental factors, large-scale variation in copy number of DNA segments recently evidenced by Bruder et al. (AJHG, 2008) showed presence of genotypic diversity in monozygotic twins. The rationale of this study was to test whether monozygotic twins display disparities of minor Histocompatibility antigens (mHags) which may play role in syngenic HCT. We and others have previously shown that mHags constitute an important immunogenetic factor influencing immune responses following transplantation from HLA-matched allogeneic donors. Patients and Methods mHags HA-1, HA-2, HA-3, HA-8, HB-1, ACC-1, ACC-2, HwA-9, HwA-10, UGT2B17, HY genotypes were defined with use of Dynal AllSet kits by PCR-SSP method in secured DNA samples from 3 monozygotic twins pairs aged 34, 24 and 28, who underwent syngenic allo-HCTs due to different hematological malignancies (NHL, CML, AML) in the Department of Hematology and BMT in Katowice, Poland in years 2000-2004. Results In 2 out of 3 syngenic pairs we have found differences in genes encoding mHags: different allele of EB-1 was present in one pair (NHL) (recipient HH, donor HY), and two different alleles of HwA-9 (RR, RG) and HwA-10 (**, R*) were present in second pair (CML). No differences in mHags were observed in the third pair (AML). Conclusions Our results question the long-standing belief that monozygotic twins are genetically identical and open up a possibility to further study the role of disparate mHags in disease and transplantation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Overexpression of the Selective Autophagy Cargo Receptor NBR1 Modifies Plant Response to Sulfur Deficit

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 669 ◽  
Author(s):  
Leszek Tarnowski ◽  
Milagros Collados Rodriguez ◽  
Jerzy Brzywczy ◽  
Dominik Cysewski ◽  
Anna Wawrzynska ◽  
...  
Keyword(s):  
Ribosomal Proteins ◽  
Kinase Inhibitors ◽  
Biological Significance ◽  
Direct Interaction ◽  
Ribosomal Gene ◽  
Plant Response ◽  
Wild Type ◽  
Selective Autophagy ◽  
Cargo Receptor

Plants exposed to sulfur deficit elevate the transcription of NBR1 what might reflect an increased demand for NBR1 in such conditions. Therefore, we investigated the role of this selective autophagy cargo receptor in plant response to sulfur deficit (-S). Transcriptome analysis of the wild type and NBR1 overexpressing plants pointed out differences in gene expression in response to -S. Our attention focused particularly on the genes upregulated by -S in roots of both lines because of significant overrepresentation of cytoplasmic ribosomal gene family. Moreover, we noticed overrepresentation of the same family in the set of proteins co-purifying with NBR1 in -S. One of these ribosomal proteins, RPS6 was chosen for verification of its direct interaction with NBR1 and proven to bind outside the NBR1 ubiquitin binding domains. The biological significance of this novel interaction and the postulated role of NBR1 in ribosomes remodeling in response to starvation remain to be further investigated. Interestingly, NBR1 overexpressing seedlings have significantly shorter roots than wild type when grown in nutrient deficient conditions in the presence of TOR kinase inhibitors. This phenotype probably results from excessive autophagy induction by the additive effect of NBR1 overexpression, starvation, and TOR inhibition.

scholarly journals Transcriptome analysis of the role of autophagy in plant response to heat stress

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0247783
Author(s):  
Yan Zhang ◽  
Haoxuan Min ◽  
Chengchen Shi ◽  
Gengshou Xia ◽  
Zhibing Lai
Keyword(s):  
Gene Expression ◽  
Heat Stress ◽  
Heat Tolerance ◽  
Stress Responses ◽  
Critical Role ◽  
Plant Response ◽  
Wild Type ◽  
Altered Expression ◽  
Regulated Gene Expression

Autophagy plays a critical role in plant heat tolerance in part by targeting heat-induced nonnative proteins for degradation. Autophagy also regulates metabolism, signaling and other processes and it is less understood how the broad function of autophagy affects plant heat stress responses. To address this issue, we performed transcriptome profiling of Arabidopsis wild-type and autophagy-deficient atg5 mutant in response to heat stress. A large number of differentially expressed genes (DEGs) were identified between wild-type and atg5 mutant even under normal conditions. These DEGs are involved not only in metabolism, hormone signaling, stress responses but also in regulation of nucleotide processing and DNA repair. Intriguingly, we found that heat treatment resulted in more robust changes in gene expression in wild-type than in the atg5 mutant plants. The dampening effect of autophagy deficiency on heat-regulated gene expression was associated with already altered expression of many heat-regulated DEGs prior to heat stress in the atg5 mutant. Altered expression of a large number of genes involved in metabolism and signaling in the autophagy mutant prior to heat stress may affect plant response to heat stress. Furthermore, autophagy played a positive role in the expression of defense- and stress-related genes during the early stage of heat stress responses but had little effect on heat-induced expression of heat shock genes. Taken together, these results indicate that the broad role of autophagy in metabolism, cellular homeostasis and other processes can also potentially affect plant heat stress responses and heat tolerance.

scholarly journals Proteasomal Components Required for Cell Growth and Stress Responses in the Haloarchaeon Haloferax volcanii

2008 ◽  
Vol 190 (24) ◽  
pp. 8096-8105 ◽  
Author(s):  
Guangyin Zhou ◽  
David Kowalczyk ◽  
Matthew A. Humbard ◽  
Sunil Rohatgi ◽  
Julie A. Maupin-Furlow
Keyword(s):  
Stress Responses ◽  
Gene Knockout ◽  
Inorganic Nitrogen ◽  
Nitrogen Sources ◽  
Genetic System ◽  
Haloferax Volcanii ◽  
Double Knockout ◽  
Genes Encoding ◽  
Proteasome Gene

ABSTRACT Little is known regarding the biological roles of archaeal proteases. The haloarchaeon Haloferax volcanii is an ideal model for understanding these enzymes, as it is one of few archaea with an established genetic system. In this report, a series of H. volcanii mutant strains with markerless and/or conditional knockouts in each known proteasome gene was systematically generated and characterized. This included single and double knockouts of genes encoding the 20S core α1 (psmA), β (psmB), and α2 (psmC) subunits as well as genes (panA and panB) encoding proteasome-activating nucleotidase (PAN) proteins closely related to the regulatory particle triple-A ATPases (Rpt) of eukaryotic 26S proteasomes. Our results demonstrate that 20S proteasomes are required for growth. Although synthesis of 20S proteasomes containing either α1 or α2 could be separately abolished via gene knockout with little to no impact on growth, conditional depletion of either β alone or α1 and α2 together rendered the cells inviable. In contrast, the PAN proteins were not essential based on the robust growth of the panA panB double knockout strain. Deletion of genes encoding either α1 or PanA did, however, render cells more sensitive to growth on organic versus inorganic nitrogen sources and hypo-osmotic stress and limited growth in the presence of l-canavanine. Abolishment of α1 synthesis also had a severe impact on the ability of cells to withstand thermal stress. This contrasted with what was seen for panA knockouts, which displayed enhanced thermotolerance. Together, these results provide new and important insight into the biological role of proteasomes in archaea.

Abstract 30: Nub1l Suppresses Neddylation And Enhances Misfolded Protein Clearance In Cardiomyocytes

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Huabo Su ◽  
Jie Li ◽  
Wenxia Ma ◽  
Ning Hou ◽  
Faqian Li
Keyword(s):  
Quality Control ◽  
Protein Degradation ◽  
Cardiac Disease ◽  
Protein Modification ◽  
Protein Quality ◽  
Ischemia Reperfusion ◽  
Protein Quality Control ◽  
Misfolded Protein ◽  
Dependent Manner

Protein modification by ubiquitin (Ub) or Ub-like proteins such as NEDD8 (neddylation) constitutes a fundamental regulatory mechanism of protein function. In contrast to well-recognized role of Ub in protein degradation, little is known about the role of NEDD8 in protein quality control. We have previously revealed that CM-restricted inactivation of deneddylation, a process that removes NEDD8 from modified proteins, accumulates neddylated proteins and impairs proteasomal and autophagic proteolysis. Here we report that proteasome inhibitors, simulated ischemia/reperfusion and H2O2 significantly increase NEDD8 conjugates in cardiomyocytes (CMs). Immunoprecipitation analysis reveals mixed modification of these proteins by Ub and NEDD8. Expression of NEDD8 but not the conjugation-deficient mutant increases neddylated proteins and accumulates a proteasome surrogate substrate GFPu in a dose-dependent manner, suggesting that excessive neddylation disrupts proteasomal proteolysis. We further targets to NUB1L, a UBL (Ub-like domain)-UBA (Ub associating domain) family protein that was shown to negatively regulate neddylation. NUB1L expression markedly reduces free NEDD8 by promoting its degradation, and abrogates proteasome inhibition-induced neddylation in CMs. Suppression of neddylation by NUB1L expression enhances GFPu degradation at baseline, and attenuates GFPu accumulation upon sI/R and H2O2 treatment. Furthermore, NUB1L expression promotes, while down-regulation of NUB1L impairs, the clearance of a bona fide misfolded protein in CMs. NUB1L expression also ameliorates proteotoxic stress- and sI/R-induced CM injury. Finally, increased NEDD8 conjugates are evident in the mouse hearts of a number of cardiac disease models as well as in human failing hearts. Together, our findings suggest that excessive neddylation disrupts protein quality control and that antagonizing neddylation by NUB1L promotes misfolded protein degradation. Targeting neddylation/NUB1L could be a novel therapeutic strategy for prevention and treatment of insufficient protein quality control-associated cardiac disease.

Abstract 393: The Intercalated Disc Protein Myozap: A Novel Player in Cardiac Proteinopathy

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Ashraf Y Rangrez ◽  
Derk Frank ◽  
Liam Cassidy ◽  
Lynn Christen ◽  
Inka Geurink ◽  
...  
Keyword(s):  
Confocal Microscopy ◽  
Protein Aggregation ◽  
Protein Quality ◽  
Transcriptome Profiling ◽  
Protein Aggregates ◽  
Intercalated Disc ◽  
Protein Aggregate ◽  
General Role ◽  
Id Protein

Background: A growing number of cardiac muscle diseases are characterized by depositions of misfolded proteins, including cardiac amyloidosis and desmin-releated cardiomyopathy (DRM). The continued presence and chronic accumulation of misfolded or unfolded proteins can lead to aggregation and/or the formation of soluble peptides that are proteotoxic. This in turn leads to compromised protein quality control and precipitates a downward spiral of the cell’s ability to maintain homeostasis and may eventually result in cell death. We recently identified massive protein aggregates in the hearts of transgenic mice overexpressing the intercalated disc (ID) protein myozap (Myozap-tg). We now sought to investigate the precise composition of these aggregates and the role of Myozap in other proteinopathies such as DRM. Methods and Results: We employed multi-dimensional proteomics, transcriptomics, confocal microscopy, and molecular biology approaches to decipher the underlying causes and consequences of protein aggregate formation in Myozap-tg mice. Transcriptome profiling of these mice revealed striking upregulation of autophagy, protein synthesis, and pro-inflammatory pathways, whereas protein degradation pathways were down-regulated. Surprisingly, proteomics analyses revealed Desmin and α-crystallin B (CryAB) as the major constituents of the aggregates, which was further validated by confocal microscopy. Moreover, we identified the presence of toxic preamyloid oligomers in Myozap-tg mouse hearts, a hallmark in many protein aggregation-based diseases including DRM. Most interestingly, we also observed co-localization of Myozap with protein aggregates observed in both transgenic mouse hearts overexpressing mutant Desmin (D7) and mutant CryAB (R120G), as well as in human DRM patients. Conclusion: The present study implies a new role for Myozap, which was previously reported to affect cardiac SRF signaling: (1) Myozap accumulates in various forms of experimental and human protein aggregation cardiomyopathy, suggesting involvement in protein homoestasis. (2) The fact that Myozap is now the third ID protein (after desmin and CryAB) to cause cardiac proteinopathy points to a general role of the ID in its molecular pathogenesis.

scholarly journals Protein Acetylation Mediated by YfiQ and CobB Is Involved in the Virulence and Stress Response ofYersinia pestis

2018 ◽  
Vol 86 (6) ◽  
Author(s):  
Wanbing Liu ◽  
Yafang Tan ◽  
Shiyang Cao ◽  
Haihong Zhao ◽  
Haihong Fang ◽  
...  
Keyword(s):  
Stress Responses ◽  
Protein Modification ◽  
Acid Resistance ◽  
Major Protein ◽  
Primary Metabolism ◽  
Protein Acetylation ◽  
Content Type ◽  
Genes Encoding ◽  
Shock Proteins

ABSTRACTRecent studies revealed that acetylation is a widely used protein modification in prokaryotic organisms. The major protein acetylation acetyltransferase YfiQ and the sirtuin-like deacetylase CobB have been found to be involved in basic physiological processes, such as primary metabolism, chemotaxis, and stress responses, inEscherichia coliandSalmonella. However, little is known about protein acetylation modifications inYersinia pestis, a lethal pathogen responsible for millions of human deaths in three worldwide pandemics. Here we found thatYp_0659andYp_1760ofY. pestisencode the major protein acetylation acetyltransferase YfiQ and the sirtuin-like deacetylase CobB, respectively, which can acetylate and deacetylate PhoP enzymaticallyin vitro. Protein acetylation impairment incobBandyfiQmutants greatly decreased bacterial tolerance to cold, hot, high-salt, and acidic environments. Our comparative transcriptomic data revealed that the strongly decreased tolerance to stress stimuli was probably related to downregulation of the genes encoding the heat shock proteins (HtpG, HslV, HslR, and IbpA), cold shock proteins (CspC and CspA1), and acid resistance proteins (HdeB and AdiA). We found that the reversible acetylation mediated by CobB and YfiQ conferred attenuation of virulence, probably partially due to the decreased expression of thepsaABCDEFoperon, which encodes Psa fimbriae that play a key role in virulence ofY. pestis. This is the first report, to our knowledge, on the roles of protein acetylation modification in stress responses, biofilm formation, and virulence ofY. pestis.

DNA methylation in satellite repeats disorders

2019 ◽  
Vol 63 (6) ◽  
pp. 757-771 ◽  
Author(s):  
Claire Francastel ◽  
Frédérique Magdinier
Keyword(s):  
Dna Methylation ◽  
Human Genome ◽  
Repetitive Dna ◽  
Dna Sequences ◽  
Satellite Repeats ◽  
Tremendous Progress ◽  
Genes Encoding ◽  
Dna Elements ◽  
Near Future

Abstract Despite the tremendous progress made in recent years in assembling the human genome, tandemly repeated DNA elements remain poorly characterized. These sequences account for the vast majority of methylated sites in the human genome and their methylated state is necessary for this repetitive DNA to function properly and to maintain genome integrity. Furthermore, recent advances highlight the emerging role of these sequences in regulating the functions of the human genome and its variability during evolution, among individuals, or in disease susceptibility. In addition, a number of inherited rare diseases are directly linked to the alteration of some of these repetitive DNA sequences, either through changes in the organization or size of the tandem repeat arrays or through mutations in genes encoding chromatin modifiers involved in the epigenetic regulation of these elements. Although largely overlooked so far in the functional annotation of the human genome, satellite elements play key roles in its architectural and topological organization. This includes functions as boundary elements delimitating functional domains or assembly of repressive nuclear compartments, with local or distal impact on gene expression. Thus, the consideration of satellite repeats organization and their associated epigenetic landmarks, including DNA methylation (DNAme), will become unavoidable in the near future to fully decipher human phenotypes and associated diseases.

Dissent in the Atlantic World, 1787–1830

2018 ◽  
Author(s):  
Katherine Carté Engel
Keyword(s):  
United States ◽  
African Americans ◽  
First Amendment ◽  
Church And State ◽  
State Level ◽  
The United States ◽  
American Population ◽  
Simple Fact ◽  
General Role

The very term ‘Dissenter’ became problematic in the United States, following the passing of the First Amendment. The formal separation of Church and state embodied in the First Amendment was followed by the ending of state-level tax support for churches. None of the states established after 1792 had formal religious establishments. Baptists, Congregationalists, Presbyterians, and Methodists accounted for the majority of the American population both at the beginning and end of this period, but this simple fact masks an important compositional shift. While the denominations of Old Dissent declined relatively, Methodism grew quickly, representing a third of the population by 1850. Dissenters thus faced several different challenges. Primary among these were how to understand the idea of ‘denomination’ and also the more general role of institutional religion in a post-establishment society. Concerns about missions, and the positions of women and African Americans are best understood within this context.

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