scholarly journals Tristetraprolin/ZFP36 regulates the turnover of autoimmune-associated HLA-DQ mRNAs

2018 ◽  
Author(s):  
Laura Pisapia ◽  
Russell S. Hamilton ◽  
Federica Farina ◽  
Vito D’Agostino ◽  
Pasquale Barba ◽  
...  
Keyword(s):  
Celiac Disease ◽  
Rna Binding ◽  
Zinc Finger Protein ◽  
Rna Binding Proteins ◽  
Autoimmune Response ◽  
Affinity Binding ◽  
Hla Dq ◽  
Rnp Complex ◽  
Protein Components ◽  
Hla Dqa1

AbstractWe have previously demonstrated that the expression of HLA class II genes is regulated by the binding of a ribonucleoprotein complex that affects the mRNA processing. We identified protein components of a complex binding transcripts encoding the HLA-DR molecule. Here we investigate whether the same RNA binding proteins interact with 3’UTR of mRNAs encoding the HLA-DQ isotype. Specifically, we focused on the HLA-DQ2.5 molecule, expressed on the surface of antigen presenting cells, and representing the main susceptibility factor for celiac disease (CD). This molecule, encoded by HLA-DQA1*05 and HLA-DQB1*02 alleles, presents the antigenic gluten peptides to CD4+ T lymphocytes, activating the autoimmune response.Here, we identified an additional component of the RNP complex, Tristetraprolin (TTP) or ZFP36, a zinc-finger protein, widely described as a factor modulating mRNA stability. TTP shows high affinity binding to 3’UTR of CD-associated HLA-DQA1*05 and HLA-DQB1*02 alleles, in contrast to lower affinity binding to HLA-DQA1*01 and HLA-DQB1*05 non-CD associated alleles. Our in silico analysis, confirmed by molecular experiments, demonstrates that TTP specifically modulates the stability of the transcripts associated with celiac disease.

scholarly journals Tristetraprolin/ZFP36 Regulates the Turnover of Autoimmune-Associated HLA-DQ mRNAs

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1570 ◽  
Author(s):  
Laura Pisapia ◽  
Russell S. Hamilton ◽  
Federica Farina ◽  
Vito D’Agostino ◽  
Pasquale Barba ◽  
...  
Keyword(s):  
T Cells ◽  
Autoimmune Diseases ◽  
Zinc Finger Protein ◽  
Class Ii ◽  
Hla Class Ii ◽  
Autoimmune Response ◽  
Risk Genes ◽  
Hla Dq ◽  
Rnp Complex ◽  
Hla Dqa1

HLA class II genes encode highly polymorphic heterodimeric proteins functioning to present antigens to T cells and stimulate a specific immune response. Many HLA genes are strongly associated with autoimmune diseases as they stimulate self-antigen specific CD4+ T cells driving pathogenic responses against host tissues or organs. High expression of HLA class II risk genes is associated with autoimmune diseases, influencing the strength of the CD4+ T-mediated autoimmune response. The expression of HLA class II genes is regulated at both transcriptional and post-transcriptional levels. Protein components of the RNP complex binding the 3′UTR and affecting mRNA processing have previously been identified. Following on from this, the regulation of HLA-DQ2.5 risk genes, the main susceptibility genetic factor for celiac disease (CD), was investigated. The DQ2.5 molecule, encoded by HLA-DQA1*05 and HLA-DQB1*02 alleles, presents the antigenic gluten peptides to CD4+ T lymphocytes, activating the autoimmune response. The zinc-finger protein Tristetraprolin (TTP) or ZFP36 was identified to be a component of the RNP complex and has been described as a factor modulating mRNA stability. The 3′UTR of CD-associated HLA-DQA1*05 and HLA-DQB1*02 mRNAs do not contain canonical TTP binding consensus sequences, therefore an in silico approach focusing on mRNA secondary structure accessibility and stability was undertaken. Key structural differences specific to the CD-associated mRNAs were uncovered, allowing them to strongly interact with TTP through their 3′UTR, conferring a rapid turnover, in contrast to lower affinity binding to HLA non-CD associated mRNA.

scholarly journals Nuclear RNP complex assembly initiates cytoplasmic RNA localization

2004 ◽  
Vol 165 (2) ◽  
pp. 203-211 ◽  
Author(s):  
Tracy L. Kress ◽  
Young J. Yoon ◽  
Kimberly L. Mowry
Keyword(s):  
Protein Interactions ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Rna Localization ◽  
Rna Sequences ◽  
Cytoplasmic Rna ◽  
Rnp Complex ◽  
Maternal Mrnas ◽  
Protein Components

Cytoplasmic localization of mRNAs is a widespread mechanism for generating cell polarity and can provide the basis for patterning during embryonic development. A prominent example of this is localization of maternal mRNAs in Xenopus oocytes, a process requiring recognition of essential RNA sequences by protein components of the localization machinery. However, it is not yet clear how and when such protein factors associate with localized RNAs to carry out RNA transport. To trace the RNA–protein interactions that mediate RNA localization, we analyzed RNP complexes from the nucleus and cytoplasm. We find that an early step in the localization pathway is recognition of localized RNAs by specific RNA-binding proteins in the nucleus. After transport into the cytoplasm, the RNP complex is remodeled and additional transport factors are recruited. These results suggest that cytoplasmic RNA localization initiates in the nucleus and that binding of specific RNA-binding proteins in the nucleus may act to target RNAs to their appropriate destinations in the cytoplasm.

Celiac disease risk stratification based on HLA-DQ heterodimer (HLA-DQA1 ~ DQB1) typing in a large cohort of adults with suspected celiac disease

2020 ◽  
Vol 81 (2-3) ◽  
pp. 59-64 ◽  
Author(s):  
Rok Seon Choung ◽  
John R. Mills ◽  
Melissa R. Snyder ◽  
Joseph A. Murray ◽  
Manish J. Gandhi
Keyword(s):  
Celiac Disease ◽  
Risk Stratification ◽  
Disease Risk ◽  
Large Cohort ◽  
Hla Dq ◽  
Hla Dqa1

scholarly journals Evidence for a primary association of celiac disease to a particular HLA-DQ alpha/beta heterodimer.

1989 ◽  
Vol 169 (1) ◽  
pp. 345-350 ◽  
Author(s):  
L M Sollid ◽  
G Markussen ◽  
J Ek ◽  
H Gjerde ◽  
F Vartdal ◽  
...  
Keyword(s):  
Celiac Disease ◽  
Oligonucleotide Probes ◽  
Hla Dq ◽  
Allele Specific ◽  
In Trans ◽  
Dqb1 Gene ◽  
Alpha Beta ◽  
Hla Dqa1 ◽  
In Cis ◽  
Dqb1 Allele

Typing of DNA from 94 unrelated children with celiac disease (CD) with HLA-DQA1 and -DQB1 allele-specific oligonucleotide probes revealed that all but one (i.e., 98.9%) may share a particular combination of a DQA1 and a DQB1 gene. These genes are arranged in cis position on the DR3DQw2 haplotype and in trans position in DR5DQw7/DR7DQw2 heterozygous individuals. Thus, most CD patients may share the same cis- or trans-encoded HLA-DQ alpha/beta heterodimer.

scholarly journals The importance of genetic factors in the development of celiac disease in children of the Uzbek population

2020 ◽  
pp. 22-27
Author(s):  
Z.M. Abdujabarova ◽  
◽  
A.T. Kamilova ◽  
Keyword(s):  
Celiac Disease ◽  
Relative Risk ◽  
Medical Center ◽  
Class Ii ◽  
Control Group ◽  
Population Genetic Study ◽  
Hla Dq ◽  
Sick Children ◽  
Hla Dqa1 ◽  
Relationship Of

The results of genetic studies have proven the relationship of celiac disease with class II genes of the major histocompatibility complex (HLA), in particular with the DQ locus. The presence of specific alleles at the HLA-DQ locus is necessary, but insufficient, for the realization of the disease phenotype. In Uzbekistan, the distribution of HLA markers in children with celiac disease has not been studied and these studies are required. Purpose — to establish the peculiarities of the distribution of HLA II class celiac disease alleles in children in the Uzbek population. Materials and methods. We examined 54 children with celiac disease of the Uzbek population, who were registered and receiving inpatient treatment at the Republican Specialized Scientific and Practical Medical Center of Pediatrics. The age of the examined children was from 1 to 14 years old, the average age was 7.3±1.9 years. The control group consisted of 109 unrelated Uzbeks without immune diseases. Molecular typing of HLA II class genes was determined by DNA chain reaction polymerase. Results. As a result of gene typing, 48 (88.8%) out of 54 investigated had DQ2 and DQ8 haplotypes associated with celiac disease. Haplotypes with only DQ2 and DQ8 were found in 19 (39.5%) and 7 (14.5%), respectively. DQ2 from 48 children was found in 18 (37.5%) children in the trans-position, in 2 (4,1%) — as two copies of DQ2 dimers, and in 1 (2%) case in combination with DQ8. Only in one case (2%) was DQ8 found as two copies of DQ8 dimers. The frequency of occurrence of the HLA-DRB1*07 and *13 alleles was significantly higher than in the control group. The maximum value of the relative risk and the criterion of reliability are noted in the DQA1*0501 allele, i.e. it is positively associated with celiac disease (χ2=7.28, RR=2.03). Significance criterion and relative risk were observed in sick children with DQB1*0201 (χ2=6.74, RR=1.97) associated with celiac disease. The number of haplotype (DQA1*0501-DQB1*0201) was 36 (75%). Conclusions. A specific predisposition to celiac disease in children of the Uzbek population is associated with the genes HLA-DQA1*0501, HLA-DQB1*0201, HLA-DRB1*07 and *13. Alleles such as DRB1*15, DQA1*0102, DQB1*0303 and *0502, have a protective effect in the development of celiac disease in children of the Uzbek population. A high frequency of carriage of the DRB1*13 — HLA-DQА1*0501 and DQB1*0201 (DQ2 type) haplotype in Uzbeks (75%) was found, which requires a more thorough population genetic study of the Uzbek population for the HLA II class DRB1-DQA1-DQB1 genes. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of these Institutes. The informed consent of the patient was obtained for conducting the studies. No conflict of interest was declared by the authors. Key words: celiac disease, children, genetics, HLA class II.

scholarly journals Suppression of C9orf72 RNA repeat-induced neurotoxicity by the ALS-associated RNA-binding protein Zfp106

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Barbara Celona ◽  
John von Dollen ◽  
Sarat C Vatsavayai ◽  
Risa Kashima ◽  
Jeffrey R Johnson ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Binding Proteins ◽  
Rna Binding ◽  
Zinc Finger Protein ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Affinity Purification ◽  
Rna Binding Protein ◽  
Severe Motor ◽  
Affinity Purification Mass Spectrometry

Expanded GGGGCC repeats in the first intron of the C9orf72 gene represent the most common cause of familial amyotrophic lateral sclerosis (ALS), but the mechanisms underlying repeat-induced disease remain incompletely resolved. One proposed gain-of-function mechanism is that repeat-containing RNA forms aggregates that sequester RNA binding proteins, leading to altered RNA metabolism in motor neurons. Here, we identify the zinc finger protein Zfp106 as a specific GGGGCC RNA repeat-binding protein, and using affinity purification-mass spectrometry, we show that Zfp106 interacts with multiple other RNA binding proteins, including the ALS-associated factors TDP-43 and FUS. We also show that Zfp106 knockout mice develop severe motor neuron degeneration, which can be suppressed by transgenic restoration of Zfp106 specifically in motor neurons. Finally, we show that Zfp106 potently suppresses neurotoxicity in a Drosophila model of C9orf72 ALS. Thus, these studies identify Zfp106 as an RNA binding protein with important implications for ALS.

scholarly journals ZFP207 controls pluripotency by multiple post-transcriptional mechanisms

2021 ◽  
Author(s):  
Sandhya Malla ◽  
Devi Prasad Bhattarai ◽  
Dario Melguizo-Sanchis ◽  
Ionut Atanasoai ◽  
Paula Groza ◽  
...  
Keyword(s):  
Rna Binding ◽  
Zinc Finger Protein ◽  
Rna Binding Proteins ◽  
Embryonic Stem ◽  
Human Escs ◽  
Neural Fate ◽  
Functional Analyses ◽  
Mammalian Embryonic Development ◽  
Essential Transcription Factor

AbstractThe pluripotent state is not solely governed by the action of the core transcription factors Oct4, Sox2, and Nanog, but also by a series of co-transcriptional and post-transcriptional events, including alternative splicing (AS) and the interaction of RNA-binding proteins (RBPs) with defined subpopulations of RNAs. Zinc Finger Protein 207 (ZFP207) is an essential transcription factor for mammalian embryonic development. Here, we employ multiple functional analyses to characterize the role of ZFP207 in mouse embryonic stem cells (ESCs). We find that ZFP207 plays a pivotal role in ESC maintenance, and silencing of Zfp207 leads to severe neuroectodermal differentiation defects. In striking contrast to human ESCs, ZFP207 does not transcriptionally regulate stem cell and neuronal-related genes but exerts its effects by control AS networks and acting as an RBP. Our study expands the role of ZFP207 to maintain ESC identity, and underscores ZFP207 functional versatility with key roles in neural fate commitment.

scholarly journals The Tristetraprolin Family of RNA-Binding Proteins in Cancer: Progress and Future Prospects

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1539 ◽  
Author(s):  
Yogesh Saini ◽  
Jian Chen ◽  
Sonika Patial
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Zinc Finger ◽  
Binding Proteins ◽  
Rna Binding ◽  
Zinc Finger Protein ◽  
Rna Binding Proteins ◽  
Regulation Of Gene Expression ◽  
Finger Protein ◽  
Post Transcriptional Regulation

Post-transcriptional regulation of gene expression plays a key role in cellular proliferation, differentiation, migration, and apoptosis. Increasing evidence suggests dysregulated post-transcriptional gene expression as an important mechanism in the pathogenesis of cancer. The tristetraprolin family of RNA-binding proteins (RBPs), which include Zinc Finger Protein 36 (ZFP36; commonly referred to as tristetraprolin (TTP)), Zinc Finger Protein 36 like 1 (ZFP36L1), and Zinc Finger Protein 36 like 2 (ZFP36L2), play key roles in the post-transcriptional regulation of gene expression. Mechanistically, these proteins function by binding to the AU-rich elements within the 3′-untranslated regions of their target mRNAs and, in turn, increasing mRNA turnover. The TTP family RBPs are emerging as key regulators of multiple biological processes relevant to cancer and are aberrantly expressed in numerous human cancers. The TTP family RBPs have tumor-suppressive properties and are also associated with cancer prognosis, metastasis, and resistance to chemotherapy. Herein, we summarize the various hallmark molecular traits of cancers that are reported to be regulated by the TTP family RBPs. We emphasize the role of the TTP family RBPs in the regulation of trait-associated mRNA targets in relevant cancer types/cell lines. Finally, we highlight the potential of the TTP family RBPs as prognostic indicators and discuss the possibility of targeting these TTP family RBPs for therapeutic benefits.

scholarly journals POS-1 and GLD-1 repress glp-1 translation through a conserved binding-site cluster

2012 ◽  
Vol 23 (23) ◽  
pp. 4473-4483 ◽  
Author(s):  
Brian M. Farley ◽  
Sean P. Ryder
Keyword(s):  
Cell Fate ◽  
Binding Sites ◽  
Rna Binding ◽  
Zinc Finger Protein ◽  
Rna Binding Proteins ◽  
Mrna Translation ◽  
Regulatory Elements ◽  
Regulatory Sequence ◽  
Regulatory Pathways ◽  
Fate Specification

RNA-binding proteins (RBPs) coordinate cell fate specification and differentiation in a variety of systems. RNA regulation is critical during oocyte development and early embryogenesis, in which RBPs control expression from maternal mRNAs encoding key cell fate determinants. The Caenorhabditis elegans Notch homologue glp-1 coordinates germline progenitor cell proliferation and anterior fate specification in embryos. A network of sequence-specific RBPs is required to pattern GLP-1 translation. Here, we map the cis-regulatory elements that guide glp-1 regulation by the CCCH-type tandem zinc finger protein POS-1 and the STAR-domain protein GLD-1. Our results demonstrate that both proteins recognize the glp-1 3′ untranslated region (UTR) through adjacent, overlapping binding sites and that POS-1 binding excludes GLD-1 binding. Both factors are required to repress glp-1 translation in the embryo, suggesting that they function in parallel regulatory pathways. It is intriguing that two equivalent POS-1–binding sites are present in the glp-1 3′ UTR, but only one, which overlaps with a translational derepression element, is functional in vivo. We propose that POS-1 regulates glp-1 mRNA translation by blocking access of other RBPs to a key regulatory sequence.

scholarly journals Comparative poly(A)+ RNA interactome capture of fission yeast RNA exosome mutants reveals insights into RNA biogenesis

2020 ◽  
Author(s):  
Adrien Birot ◽  
Cornelia Kilchert ◽  
Krzysztof Kus ◽  
Emily Priest ◽  
Ahmad Al Alwash ◽  
...  
Keyword(s):  
Quality Control ◽  
Rna Polymerase Ii ◽  
Rna Binding ◽  
Zinc Finger Protein ◽  
Rna Binding Proteins ◽  
Protein Coding ◽  
Multiple Protein ◽  
Nuclear Rna ◽  
Control Step ◽  
Rna Exosome

ABSTRACTThe nuclear RNA exosome plays a key role in quality control and processing of multiple protein-coding and non-coding transcripts made by RNA polymerase II. A mechanistic understanding of exosome function remains a challenge given it has multiple roles in RNA regulation. Here we have analysed changes in the poly(A)+ RNA transcriptome and interactome provoked by mutations in three distinct subunits of the nuclear RNA exosome. We have identified multiple proteins whose occupancy on RNA is altered in the exosome mutants. We demonstrate that the Zinc-finger protein Mub1 regulates exosome dependent transcripts that encode stress-responsive proteins. Furthermore, we assess impact of the exosome inactivation upon RNA binding of the components of the mRNA processing machineries such as spliceosome and mRNA cleavage polyadenylation complex. We show that mutations in the exosome lead to accumulation of the components of U1 and U2 snRNPs on poly(A)+ RNA and depletion of the components of the activated spliceosome from RNA suggesting that the early stages of spliceosome assembly might provide a critical quality control step. Collectively, our data provide a global view of how RNA metabolism is affected in the exosome-deficient cells and reveal RNA-binding proteins that may act as novel exosome cofactors.

Sign in / Sign up

Export Citation Format

Share Document