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...
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todo:paper_00219258_v289_n46_p31792_Lu2023-10-03T14:23:23Z Hu antigen R (HuR) is a positive regulator of the RNA-binding proteins TDP-43 and FUS/TLS: Implications for amyotrophic lateral sclerosis Lu, L. Zheng, L. Si, Y. Luo, W. Dujardin, G. Kwan, T. Potochick, N.R. Thompson, S.R. Schneider, D.A. King, P.H. 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. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar 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 Lu, L. Zheng, L. Si, Y. Luo, W. Dujardin, G. Kwan, T. Potochick, N.R. Thompson, S.R. Schneider, D.A. King, P.H. 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. |
| format |
JOUR |
| author |
Lu, L. Zheng, L. Si, Y. Luo, W. Dujardin, G. Kwan, T. Potochick, N.R. Thompson, S.R. Schneider, D.A. King, P.H. |
| author_facet |
Lu, L. Zheng, L. Si, Y. Luo, W. Dujardin, G. Kwan, T. Potochick, N.R. Thompson, S.R. Schneider, D.A. King, P.H. |
| author_sort |
Lu, L. |
| 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 |
| url |
http://hdl.handle.net/20.500.12110/paper_00219258_v289_n46_p31792_Lu |
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