Hu antigen R (HuR) is a positive regulator of the RNA-binding proteins TDP-43 and FUS/TLS: Implications for amyotrophic lateral sclerosis

Posttranscriptional gene regulation is governed by a network of RNA-binding proteins (RBPs) that interact with regulatory elements in the mRNA to modulate multiple molecular processes, including splicing, RNA transport, RNA stability, and translation. Mounting evidence indicates that there is a hier...

Descripción completa

Guardado en:
Detalles Bibliográficos
Publicado: 2014
Materias:
RNA
Acceso en línea:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00219258_v289_n46_p31792_Lu
http://hdl.handle.net/20.500.12110/paper_00219258_v289_n46_p31792_Lu
Aporte de:
id paper:paper_00219258_v289_n46_p31792_Lu
record_format dspace
spelling paper:paper_00219258_v289_n46_p31792_Lu2023-06-08T14:43:36Z Hu antigen R (HuR) is a positive regulator of the RNA-binding proteins TDP-43 and FUS/TLS: Implications for amyotrophic lateral sclerosis Gene expression Genes Neurodegenerative diseases Neurons Proteins RNA Amyotrophic lateral sclerosis Conditioned medium Molecular process Post-transcriptional gene regulation Regulatory elements RNA-binding protein Translational efficiencies Untranslated regions Nucleic acids cystic fibrosis transmembrane conductance regulator fused in sarcoma protein Hu antigen R RNA binding protein TAR DNA binding protein unclassified drug 3' untranslated region CFTR protein, human culture medium cystic fibrosis transmembrane conductance regulator DNA binding protein ELAVL1 protein, human Hu antigen protein TDP-43 RNA RNA binding protein 3' untranslated region amyotrophic lateral sclerosis animal cell Article astrocyte autoregulation binding affinity biotinylation cell viability controlled study densitometry immunoprecipitation motoneuron mouse nonhuman open reading frame phenotype polyadenylation polysome protein analysis protein binding protein expression protein function RNA isolation RNA processing amyotrophic lateral sclerosis animal anoxia cell line cell survival chemistry culture medium cytology gene expression regulation genetics human metabolism tumor cell line 3' Untranslated Regions Amyotrophic Lateral Sclerosis Animals Anoxia Astrocytes Cell Line Cell Line, Tumor Cell Survival Culture Media, Conditioned Cystic Fibrosis Transmembrane Conductance Regulator DNA-Binding Proteins Gene Expression Regulation Hu Paraneoplastic Encephalomyelitis Antigens Humans Mice Motor Neurons Phenotype RNA RNA-Binding Protein FUS Posttranscriptional gene regulation is governed by a network of RNA-binding proteins (RBPs) that interact with regulatory elements in the mRNA to modulate multiple molecular processes, including splicing, RNA transport, RNA stability, and translation. Mounting evidence indicates that there is a hierarchy within this network whereby certain RBPs cross-regulate other RBPs to coordinate gene expression. HuR, an RNA-binding protein we linked previously to aberrant VEGF mRNA metabolism in models of SOD1-associated amyotrophic lateral sclerosis, has been identified as being high up in this hierarchy, serving as a regulator of RNA regulators. Here we investigated the role of HuR in regulating two RBPs, TDP-43 and FUS/TLS, that have been linked genetically to amyotrophic lateral sclerosis. Wefound thatHuRpromotes the expression of both RBPs in primary astrocytes and U251 cells under normal and stressed (hypoxic) conditions. For TDP-43, we found that HuR binds to the 3' untranslated region (UTR) and regulates its expression through translational efficiency rather than RNA stability. With HuR knockdown, there was a shift of TDP-43 and FUS mRNAs away from polysomes, consistent with translational silencing. The TDP-43 splicing function was attenuated upon HuR knockdown and could be rescued by ectopic TDP-43 lacking the 3' UTR regulatory elements. Finally, conditioned medium from astrocytes in which HuR or TDP-43 was knocked down produced significant motor neuron and cortical neuron toxicity in vitro. These findings indicate that HuR regulates TDP-43 and FUS/TLS expression and that loss of HuR-mediated RNA processing in astrocytes can alter the molecular and cellular landscape to produce a toxic phenotype. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. 2014 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00219258_v289_n46_p31792_Lu http://hdl.handle.net/20.500.12110/paper_00219258_v289_n46_p31792_Lu
institution Universidad de Buenos Aires
institution_str I-28
repository_str R-134
collection Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic Gene expression
Genes
Neurodegenerative diseases
Neurons
Proteins
RNA
Amyotrophic lateral sclerosis
Conditioned medium
Molecular process
Post-transcriptional gene regulation
Regulatory elements
RNA-binding protein
Translational efficiencies
Untranslated regions
Nucleic acids
cystic fibrosis transmembrane conductance regulator
fused in sarcoma protein
Hu antigen R
RNA binding protein
TAR DNA binding protein
unclassified drug
3' untranslated region
CFTR protein, human
culture medium
cystic fibrosis transmembrane conductance regulator
DNA binding protein
ELAVL1 protein, human
Hu antigen
protein TDP-43
RNA
RNA binding protein
3' untranslated region
amyotrophic lateral sclerosis
animal cell
Article
astrocyte
autoregulation
binding affinity
biotinylation
cell viability
controlled study
densitometry
immunoprecipitation
motoneuron
mouse
nonhuman
open reading frame
phenotype
polyadenylation
polysome
protein analysis
protein binding
protein expression
protein function
RNA isolation
RNA processing
amyotrophic lateral sclerosis
animal
anoxia
cell line
cell survival
chemistry
culture medium
cytology
gene expression regulation
genetics
human
metabolism
tumor cell line
3' Untranslated Regions
Amyotrophic Lateral Sclerosis
Animals
Anoxia
Astrocytes
Cell Line
Cell Line, Tumor
Cell Survival
Culture Media, Conditioned
Cystic Fibrosis Transmembrane Conductance Regulator
DNA-Binding Proteins
Gene Expression Regulation
Hu Paraneoplastic Encephalomyelitis Antigens
Humans
Mice
Motor Neurons
Phenotype
RNA
RNA-Binding Protein FUS
spellingShingle Gene expression
Genes
Neurodegenerative diseases
Neurons
Proteins
RNA
Amyotrophic lateral sclerosis
Conditioned medium
Molecular process
Post-transcriptional gene regulation
Regulatory elements
RNA-binding protein
Translational efficiencies
Untranslated regions
Nucleic acids
cystic fibrosis transmembrane conductance regulator
fused in sarcoma protein
Hu antigen R
RNA binding protein
TAR DNA binding protein
unclassified drug
3' untranslated region
CFTR protein, human
culture medium
cystic fibrosis transmembrane conductance regulator
DNA binding protein
ELAVL1 protein, human
Hu antigen
protein TDP-43
RNA
RNA binding protein
3' untranslated region
amyotrophic lateral sclerosis
animal cell
Article
astrocyte
autoregulation
binding affinity
biotinylation
cell viability
controlled study
densitometry
immunoprecipitation
motoneuron
mouse
nonhuman
open reading frame
phenotype
polyadenylation
polysome
protein analysis
protein binding
protein expression
protein function
RNA isolation
RNA processing
amyotrophic lateral sclerosis
animal
anoxia
cell line
cell survival
chemistry
culture medium
cytology
gene expression regulation
genetics
human
metabolism
tumor cell line
3' Untranslated Regions
Amyotrophic Lateral Sclerosis
Animals
Anoxia
Astrocytes
Cell Line
Cell Line, Tumor
Cell Survival
Culture Media, Conditioned
Cystic Fibrosis Transmembrane Conductance Regulator
DNA-Binding Proteins
Gene Expression Regulation
Hu Paraneoplastic Encephalomyelitis Antigens
Humans
Mice
Motor Neurons
Phenotype
RNA
RNA-Binding Protein FUS
Hu antigen R (HuR) is a positive regulator of the RNA-binding proteins TDP-43 and FUS/TLS: Implications for amyotrophic lateral sclerosis
topic_facet Gene expression
Genes
Neurodegenerative diseases
Neurons
Proteins
RNA
Amyotrophic lateral sclerosis
Conditioned medium
Molecular process
Post-transcriptional gene regulation
Regulatory elements
RNA-binding protein
Translational efficiencies
Untranslated regions
Nucleic acids
cystic fibrosis transmembrane conductance regulator
fused in sarcoma protein
Hu antigen R
RNA binding protein
TAR DNA binding protein
unclassified drug
3' untranslated region
CFTR protein, human
culture medium
cystic fibrosis transmembrane conductance regulator
DNA binding protein
ELAVL1 protein, human
Hu antigen
protein TDP-43
RNA
RNA binding protein
3' untranslated region
amyotrophic lateral sclerosis
animal cell
Article
astrocyte
autoregulation
binding affinity
biotinylation
cell viability
controlled study
densitometry
immunoprecipitation
motoneuron
mouse
nonhuman
open reading frame
phenotype
polyadenylation
polysome
protein analysis
protein binding
protein expression
protein function
RNA isolation
RNA processing
amyotrophic lateral sclerosis
animal
anoxia
cell line
cell survival
chemistry
culture medium
cytology
gene expression regulation
genetics
human
metabolism
tumor cell line
3' Untranslated Regions
Amyotrophic Lateral Sclerosis
Animals
Anoxia
Astrocytes
Cell Line
Cell Line, Tumor
Cell Survival
Culture Media, Conditioned
Cystic Fibrosis Transmembrane Conductance Regulator
DNA-Binding Proteins
Gene Expression Regulation
Hu Paraneoplastic Encephalomyelitis Antigens
Humans
Mice
Motor Neurons
Phenotype
RNA
RNA-Binding Protein FUS
description Posttranscriptional gene regulation is governed by a network of RNA-binding proteins (RBPs) that interact with regulatory elements in the mRNA to modulate multiple molecular processes, including splicing, RNA transport, RNA stability, and translation. Mounting evidence indicates that there is a hierarchy within this network whereby certain RBPs cross-regulate other RBPs to coordinate gene expression. HuR, an RNA-binding protein we linked previously to aberrant VEGF mRNA metabolism in models of SOD1-associated amyotrophic lateral sclerosis, has been identified as being high up in this hierarchy, serving as a regulator of RNA regulators. Here we investigated the role of HuR in regulating two RBPs, TDP-43 and FUS/TLS, that have been linked genetically to amyotrophic lateral sclerosis. Wefound thatHuRpromotes the expression of both RBPs in primary astrocytes and U251 cells under normal and stressed (hypoxic) conditions. For TDP-43, we found that HuR binds to the 3' untranslated region (UTR) and regulates its expression through translational efficiency rather than RNA stability. With HuR knockdown, there was a shift of TDP-43 and FUS mRNAs away from polysomes, consistent with translational silencing. The TDP-43 splicing function was attenuated upon HuR knockdown and could be rescued by ectopic TDP-43 lacking the 3' UTR regulatory elements. Finally, conditioned medium from astrocytes in which HuR or TDP-43 was knocked down produced significant motor neuron and cortical neuron toxicity in vitro. These findings indicate that HuR regulates TDP-43 and FUS/TLS expression and that loss of HuR-mediated RNA processing in astrocytes can alter the molecular and cellular landscape to produce a toxic phenotype. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
title Hu antigen R (HuR) is a positive regulator of the RNA-binding proteins TDP-43 and FUS/TLS: Implications for amyotrophic lateral sclerosis
title_short Hu antigen R (HuR) is a positive regulator of the RNA-binding proteins TDP-43 and FUS/TLS: Implications for amyotrophic lateral sclerosis
title_full Hu antigen R (HuR) is a positive regulator of the RNA-binding proteins TDP-43 and FUS/TLS: Implications for amyotrophic lateral sclerosis
title_fullStr Hu antigen R (HuR) is a positive regulator of the RNA-binding proteins TDP-43 and FUS/TLS: Implications for amyotrophic lateral sclerosis
title_full_unstemmed Hu antigen R (HuR) is a positive regulator of the RNA-binding proteins TDP-43 and FUS/TLS: Implications for amyotrophic lateral sclerosis
title_sort hu antigen r (hur) is a positive regulator of the rna-binding proteins tdp-43 and fus/tls: implications for amyotrophic lateral sclerosis
publishDate 2014
url https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00219258_v289_n46_p31792_Lu
http://hdl.handle.net/20.500.12110/paper_00219258_v289_n46_p31792_Lu
_version_ 1768544256225443840