scholarly journals Transcriptional Regulation of CD40 Expression by 4 Ribosomal Proteins via a Functional SNP on a Disease-Associated CD40 Locus

Genes ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1526
Author(s):  
Meijuan Zou ◽  
Xiaoyu Zhang ◽  
Danli Jiang ◽  
Yihan Zhao ◽  
Ting Wu ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Ribosomal Proteins ◽  
Protein Translation ◽  
Transcriptional Regulators ◽  
Ribosomal Subunits ◽  
Risk Genes ◽  
Regulation Network ◽  
Bona Fide ◽  
Cd40 Expression ◽  
Functional Snp

Previously, using FREP-MS, we identified a protein complex including eight proteins that specifically bind to the functional SNP (fSNP) rs6032664 at a CD40 locus associated with autoimmune diseases. Among these eight proteins, four are ribosomal proteins RPL26, RPL4, RPL8, and RPS9 that normally make up the ribosomal subunits involved in the cellular process of protein translation. So far, no publication has shown these ribosomal proteins function as transcriptional regulators. In this work, we demonstrate that four ribosomal proteins: RPL26, RPL4, RPL8, and RPS9 are bona fide CD40 transcriptional regulators via binding to rs6032664. In addition, we show that suppression of CD40 expression by RPL26 RNAi knockdown inactivates NF-κB p65 by dephosphorylation via NF-κB signaling pathway in fibroblast-like synoviocytes (FLS), which further reduces the transcription of disease-associated risk genes such as STAT4, CD86, TRAF1 and ICAM1 as the direct targets of NF-κB p65. Based on these findings, a disease-associated risk gene transcriptional regulation network (TRN) is generated, in which decreased expression of, at least, RPL26 results in the downregulation of risk genes: STAT4, CD86, TRAF1 and ICAM1, as well as the two proinflammatory cytokines: IL1β and IL6 via CD40-induced NF-κB signaling. We believe that further characterization of this disease-associated TRN in the CD40-induced NF-κB signaling by identifying both the upstream and downstream regulators will potentially enable us to identify the best targets for drug development.

NSR1 is required for pre-rRNA processing and for the proper maintenance of steady-state levels of ribosomal subunits

1992 ◽  
Vol 12 (9) ◽  
pp. 3865-3871
Author(s):  
W C Lee ◽  
D Zabetakis ◽  
T Mélèse
Keyword(s):  
Nuclear Localization ◽  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Protein Translation ◽  
Striking Similarity ◽  
Growth Defect ◽  
Nuclear Localization Sequence ◽  
Rrna Processing ◽  
Ribosomal Subunits ◽  
Localization Sequence

NSR1 is a yeast nuclear localization sequence-binding protein showing striking similarity in its domain structure to nucleolin. Cells lacking NSR1 are viable but have a severe growth defect. We show here that NSR1, like nucleolin, is involved in ribosome biogenesis. The nsr1 mutant is deficient in pre-rRNA processing such that the initial 35S pre-rRNA processing is blocked and 20S pre-rRNA is nearly absent. The reduced amount of 20S pre-rRNA leads to a shortage of 18S rRNA and is reflected in a change in the distribution of 60S and 40S ribosomal subunits; there is no free pool of 40S subunits, and the free pool of 60S subunits is greatly increased in size. The lack of free 40S subunits or the improper assembly of these subunits causes the nsr1 mutant to show sensitivity to the antibiotic paromomycin, which affects protein translation, at concentrations that do not affect the growth of the wild-type strain. Our data support the idea that NSR1 is involved in the proper assembly of pre-rRNA particles, possibly by bringing rRNA and ribosomal proteins together by virtue of its nuclear localization sequence-binding domain and multiple RNA recognition motifs. Alternatively, NSR1 may also act to regulate the nuclear entry of ribosomal proteins required for proper assembly of pre-rRNA particles.

scholarly journals NSR1 is required for pre-rRNA processing and for the proper maintenance of steady-state levels of ribosomal subunits.

1992 ◽  
Vol 12 (9) ◽  
pp. 3865-3871 ◽  
Author(s):  
W C Lee ◽  
D Zabetakis ◽  
T Mélèse
Keyword(s):  
Nuclear Localization ◽  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Protein Translation ◽  
Striking Similarity ◽  
Growth Defect ◽  
Nuclear Localization Sequence ◽  
Rrna Processing ◽  
Ribosomal Subunits ◽  
Localization Sequence

NSR1 is a yeast nuclear localization sequence-binding protein showing striking similarity in its domain structure to nucleolin. Cells lacking NSR1 are viable but have a severe growth defect. We show here that NSR1, like nucleolin, is involved in ribosome biogenesis. The nsr1 mutant is deficient in pre-rRNA processing such that the initial 35S pre-rRNA processing is blocked and 20S pre-rRNA is nearly absent. The reduced amount of 20S pre-rRNA leads to a shortage of 18S rRNA and is reflected in a change in the distribution of 60S and 40S ribosomal subunits; there is no free pool of 40S subunits, and the free pool of 60S subunits is greatly increased in size. The lack of free 40S subunits or the improper assembly of these subunits causes the nsr1 mutant to show sensitivity to the antibiotic paromomycin, which affects protein translation, at concentrations that do not affect the growth of the wild-type strain. Our data support the idea that NSR1 is involved in the proper assembly of pre-rRNA particles, possibly by bringing rRNA and ribosomal proteins together by virtue of its nuclear localization sequence-binding domain and multiple RNA recognition motifs. Alternatively, NSR1 may also act to regulate the nuclear entry of ribosomal proteins required for proper assembly of pre-rRNA particles.

scholarly journals Post-GWAS functional studies reveal an RA-associated CD40 induced NF-kB signal transduction and transcriptional regulation network targeted by class II HDAC inhibitors

2021 ◽  
Author(s):  
Meijuan Zou ◽  
Danli Jiang ◽  
Ting Wu ◽  
Xiaoyu Zhang ◽  
Yihan Zhao ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Transcriptional Regulation ◽  
Target Identification ◽  
Hdac Inhibitors ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Published Data ◽  
Risk Genes ◽  
Functional Studies ◽  
Regulation Network ◽  
Transcriptional Regulation Network

Abstract Currently, it remains difficult to identify which SNPs identified by GWAS are functional, and how various functional SNPs (fSNPs) interact and contribute to disease susceptibility. GWAS have identified a CD40 locus that is associated with rheumatoid arthritis (RA). We previously used two techniques developed in our lab, SNP-seq and FREP-MS, to determine that the RA risk gene RBPJ regulates CD40 expression via a fSNP at the RA-associated CD40 locus. In the present work, by applying the same approach, we report the identification of 6 proteins that regulate RBPJ expression via binding to two fSNPs on the RA-associated RBPJ locus. Using these findings, together with published data, we constructed an RA-associated signal transduction and transcriptional regulation network (STTRN) that functionally connects multiple RA-associated risk genes via transcriptional regulation networks linked by CD40-induced NF-kB signaling. Remarkably, this STTRN provides insight into the potential mechanism of action for the histone deacetylase (HDAC) inhibitor givinostat, an approved therapy for systemic juvenile idiopathic arthritis (SJIA). Thus, generation of disease-associated STTRNs based on post-GWAS functional studies is demonstrated as a novel and effective approach to apply GWAS for mechanistic studies and target identification.

scholarly journals Rrb1p, a Yeast Nuclear WD-Repeat Protein Involved in the Regulation of Ribosome Biosynthesis

2001 ◽  
Vol 21 (4) ◽  
pp. 1260-1271 ◽  
Author(s):  
Tatiana L. Iouk ◽  
John D. Aitchison ◽  
Shawna Maguire ◽  
Richard W. Wozniak
Keyword(s):  
Transcriptional Regulation ◽  
Ribosomal Protein ◽  
Ribosome Biogenesis ◽  
Protein Translation ◽  
Environmental Cues ◽  
Ribosomal Subunits ◽  
Nuclear Extracts ◽  
Coordinated Expression ◽  
Wd Repeat ◽  
Ribosome Biosynthesis

ABSTRACT Ribosome biogenesis is regulated by environmental cues that coordinately modulate the synthesis of ribosomal components and their assembly into functional subunits. We have identified an essential yeast WD-repeat-containing protein, termed Rrb1p, that has a role in both the assembly of the 60S ribosomal subunits and the transcriptional regulation of ribosomal protein (RP) genes. Rrb1p is located in the nucleus and is concentrated in the nucleolus. Its presence is required to maintain normal cellular levels of 60S subunits, 80S ribosomes, and polyribosomes. The function of Rrb1p in ribosome biogenesis appears to be linked to its association with the ribosomal protein rpL3. Immunoprecipitation of Rrb1p from nuclear extracts revealed that it physically interacts with rpL3. Moreover, the overproduction of Rrb1p led to increases in cellular levels of free rpL3 that accumulated in the nucleus together with Rrb1p. The concentration of these proteins within the nucleus was dependent on ongoing protein translation. We also showed that overexpression of RRB1 led to an increase in the expression of RPL3 while all other examined RP genes were unaffected. In contrast, depletion of RRB1 caused an increase in the expression of all RP genes examined except RPL3. These results suggest that Rrb1p regulates RPL3 expression and uncouples it from the coordinated expression of other RP genes.

scholarly journals The transcription factor SlHY5 regulates the ripening of tomato fruit at both the transcriptional and translational levels

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Weihao Wang ◽  
Peiwen Wang ◽  
Xiaojing Li ◽  
Yuying Wang ◽  
Shiping Tian ◽  
...  
Keyword(s):  
Fruit Ripening ◽  
Nutritional Quality ◽  
Ribosomal Proteins ◽  
Anthocyanin Biosynthesis ◽  
Tomato Fruit ◽  
Critical Role ◽  
Regulation Of Gene Expression ◽  
Protein Translation ◽  
Transcriptional Level ◽  
Translation Efficiency

AbstractLight plays a critical role in plant growth and development, but the mechanisms through which light regulates fruit ripening and nutritional quality in horticultural crops remain largely unknown. Here, we found that ELONGATED HYPOCOTYL 5 (HY5), a master regulator in the light signaling pathway, is required for normal fruit ripening in tomato (Solanum lycopersicum). Loss of function of tomato HY5 (SlHY5) impairs pigment accumulation and ethylene biosynthesis. Transcriptome profiling identified 2948 differentially expressed genes, which included 1424 downregulated and 1524 upregulated genes, in the Slhy5 mutants. In addition, genes involved in carotenoid and anthocyanin biosynthesis and ethylene signaling were revealed as direct targets of SlHY5 by chromatin immunoprecipitation. Surprisingly, the expression of a large proportion of genes encoding ribosomal proteins was downregulated in the Slhy5 mutants, and this downregulation pattern was accompanied by a decrease in the abundance of ribosomal proteins. Further analysis demonstrated that SlHY5 affected the translation efficiency of numerous ripening-related genes. These data indicate that SlHY5 regulates fruit ripening both at the transcriptional level by targeting specific molecular pathways and at the translational level by affecting the protein translation machinery. Our findings unravel the regulatory mechanisms of SlHY5 in controlling fruit ripening and nutritional quality and uncover the multifaceted regulation of gene expression by transcription factors.

Control points in eucaryotic ribosome biogenesis

1991 ◽  
Vol 69 (1) ◽  
pp. 5-22 ◽  
Author(s):  
D. E. Larson ◽  
P. Zahradka ◽  
B. H. Sells
Keyword(s):  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Rna Polymerase Iii ◽  
Ribosomal Subunits ◽  
Rrna Species ◽  
Polymerase I ◽  
Ribosomal Precursor ◽  
Precursor Molecules

Ribosome biogenesis in eucaryotic cells involves the coordinated synthesis of four rRNA species, transcribed by RNA polymerase I (18S, 28S, 5.8S) and RNA polymerase III (5S), and approximately 80 ribosomal proteins translated from mRNAs synthesized by RNA polymerase II. Assembly of the ribosomal subunits in the nucleolus, the site of 45S rRNA precursor gene transcription, requires the movement of 5S rRNA and ribosomal proteins from the nucleoplasm and cytoplasm, respectively, to this structure. To integrate these events and ensure the balanced production of individual ribosomal components, different strategies have been developed by eucaryotic organisms in response to a variety of physiological changes. This review presents an overview of the mechanisms modulating the production of ribosomal precursor molecules and the rate of ribosome biogenesis in various biological systems.Key words: rRNA, ribosomal proteins, nucleolus, ribosome.

Evidence for a nuclear passage of nascent polypeptide-associated complex subunits in yeast

2001 ◽  
Vol 114 (14) ◽  
pp. 2641-2648
Author(s):  
Jacqueline Franke ◽  
Barbara Reimann ◽  
Enno Hartmann ◽  
Matthias Köhler ◽  
Brigitte Wiedmann
Keyword(s):  
Transcriptional Regulation ◽  
Steady State ◽  
Fluorescence Microscopy ◽  
Nuclear Import ◽  
Cell Fractionation ◽  
Active Process ◽  
Ribosomal Subunits ◽  
State Equilibrium ◽  
Nascent Polypeptide ◽  
Ribosome Binding

The nascent polypeptide-associated complex (NAC) has been found quantitatively associated with ribosomes in the cytosol by means of cell fractionation or fluorescence microscopy. There have been reports, however, that single NAC subunits may be involved in transcriptional regulation. We reasoned that the cytosolic location might only reflect a steady state equilibrium and therefore investigated the yeast NAC proteins for their ability to enter the nucleus. We found that single subunits of yeast NAC can indeed be transported into the nucleus and that this transport is an active process depending on different nuclear import factors. Translocation into the nucleus was only observed when binding to ribosomes was inhibited. We identified a domain of the ribosome-binding NAC subunit essential for nuclear import via the importin Kap123p/Pse1p-dependent import route. We hypothesize that newly translated NAC proteins travel into the nucleus to bind stoichiometrically to ribosomal subunits and then leave the nucleus together with these subunits to concentrate in the cytosol.

Ribosomal protein S14 is altered by two-step emetine resistance mutations in Chinese hamster cells

1983 ◽  
Vol 3 (2) ◽  
pp. 190-197
Author(s):  
J J Madjar ◽  
M Frahm ◽  
S McGill ◽  
D J Roufa
Keyword(s):  
Ribosomal Protein ◽  
Ribosomal Proteins ◽  
Ribosomal Subunit ◽  
Chinese Hamster ◽  
Complementation Group ◽  
Resistance Mutations ◽  
Cho Cell ◽  
Ribosomal Subunits ◽  
40S Ribosomal Subunit ◽  
One Step

Four two-dimensional polyacrylamide gel electrophoresis systems were used to identify 78 Chinese hamster cell ribosomal proteins by the uniform nomenclature based on rat liver ribosomal proteins. The 40S ribosomal subunit protein affected by Chinese hamster ovary (CHO) cell one-step emetine resistance mutations is designated S14 in the standard nomenclature. To seek unambiguous genetic evidence for a cause and effect relationship between CHO cell emetine resistance and mutations in the S14 gene, we mutagenized a one-step CHO cell mutant and isolated second-step mutant clones resistant to 10-fold-higher concentrations of emetine. All of the highly resistant, two-step CHO cell mutants obtained displayed additional alterations in ribosomal protein S14. Hybridization complementation tests revealed that the two-step CHO cell emetine resistance mutants were members of the same complementation group defined by one-step CHO cell mutants, EmtB. Two-step mutants obtained from a Chinese hamster lung cell emetine-resistant clone belong to the EmtA complementation group. The two-step and EmtB mutants elaborated 40S ribosomal subunits, which dissociated to 32S and 40S core particles in buffers containing 0.5 M KCl at 4 degrees C. In contrast, 40S ribosomal subunits purified from all EmtA, one-step EmtB EmtC mutants, and wild-type CHO and lung cells were stable at this temperature in buffers containing substantially higher concentrations of salt. Thus, two-step emtB mutations affect the structure of S14 protein directly and the stability of the 40S ribosomal subunit indirectly.

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