Artículo

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" (2014) Journal of Biological Chemistry. 289(46):31792-31804
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Abstract:

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.

Registro:

Documento: Artículo
Título:Hu antigen R (HuR) is a positive regulator of the RNA-binding proteins TDP-43 and FUS/TLS: Implications for amyotrophic lateral sclerosis
Autor:Lu, L.; Zheng, L.; Si, Y.; Luo, W.; Dujardin, G.; Kwan, T.; Potochick, N.R.; Thompson, S.R.; Schneider, D.A.; King, P.H.
Filiación:Department of Neurology, University of Alabama at Birmingham, Sparks Center, 1720 7th Ave. S., Birmingham, AL 35294, 35233-0017, United States
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, United States
Department of Cell, Developmental, and Integrative Biolog, University of Alabama at Birmingham, Birmingham, AL 35294, United States
Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, United States
Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, United States
Birmingham Veterans Affairs Medical Center, Birmingham, AL 35294, United States
Facultad de Ciencias Exactas, Naturales Universidad de Buenos Aires, Buenos Aires, C1428EHA, Argentina
Palabras clave: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
Año:2014
Volumen:289
Número:46
Página de inicio:31792
Página de fin:31804
DOI: http://dx.doi.org/10.1074/jbc.M114.573246
Título revista:Journal of Biological Chemistry
Título revista abreviado:J. Biol. Chem.
ISSN:00219258
CODEN:JBCHA
CAS:cystic fibrosis transmembrane conductance regulator, 126880-72-6; RNA, 63231-63-0; 3' Untranslated Regions; CFTR protein, human; Culture Media, Conditioned; Cystic Fibrosis Transmembrane Conductance Regulator; DNA-Binding Proteins; ELAVL1 protein, human; Hu Paraneoplastic Encephalomyelitis Antigens; protein TDP-43; RNA; RNA-Binding Protein FUS
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00219258_v289_n46_p31792_Lu

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Citas:

---------- APA ----------
Lu, L., Zheng, L., Si, Y., Luo, W., Dujardin, G., Kwan, T., Potochick, N.R.,..., King, P.H. (2014) . Hu antigen R (HuR) is a positive regulator of the RNA-binding proteins TDP-43 and FUS/TLS: Implications for amyotrophic lateral sclerosis. Journal of Biological Chemistry, 289(46), 31792-31804.
http://dx.doi.org/10.1074/jbc.M114.573246
---------- CHICAGO ----------
Lu, L., Zheng, L., Si, Y., Luo, W., Dujardin, G., Kwan, T., et al. "Hu antigen R (HuR) is a positive regulator of the RNA-binding proteins TDP-43 and FUS/TLS: Implications for amyotrophic lateral sclerosis" . Journal of Biological Chemistry 289, no. 46 (2014) : 31792-31804.
http://dx.doi.org/10.1074/jbc.M114.573246
---------- MLA ----------
Lu, L., Zheng, L., Si, Y., Luo, W., Dujardin, G., Kwan, T., et al. "Hu antigen R (HuR) is a positive regulator of the RNA-binding proteins TDP-43 and FUS/TLS: Implications for amyotrophic lateral sclerosis" . Journal of Biological Chemistry, vol. 289, no. 46, 2014, pp. 31792-31804.
http://dx.doi.org/10.1074/jbc.M114.573246
---------- VANCOUVER ----------
Lu, L., Zheng, L., Si, Y., Luo, W., Dujardin, G., Kwan, T., et al. Hu antigen R (HuR) is a positive regulator of the RNA-binding proteins TDP-43 and FUS/TLS: Implications for amyotrophic lateral sclerosis. J. Biol. Chem. 2014;289(46):31792-31804.
http://dx.doi.org/10.1074/jbc.M114.573246