Hu antigen R (HuR) functions as an alternative pre-mRNA splicing regulator of Fas apoptosis-promoting receptor on exon definition.
Exclusion of exon 6 by alternative RNA splicing of the primary transcript of the apoptosis receptor Fas produces a soluble isoform that prevents programmed cell death. I report that antiapoptotic regulator Hu antigen R (HuR, ELAVL1), a member of the embryonic lethal, abnormal vision, Drosophila-like (ELAVL) family, promotes Fas exon 6 skipping by binding to an exonic splicing silencer. HuR inhibits the association of U2 small nuclear ribonucleoprotein (snRNP) auxiliary factor 65 kDa (U2AF65) with the upstream 3' splice site, without decreasing recognition of the downstream 5' splice site by U1 snRNP but by antagonizing the role of TIA-1 (T-cell intracellular antigen 1)/TIAR (TIA-1 related protein) on exon definition. Remarkably, U1 snRNP-mediated recognition of the 5' splice site is partially required for efficient U2AF65 inhibition. Further, the silencing capacity of HuR as splicing regulator resides in the RRM1 and hinge-RRM3 domains. Taken together, these results support a functional link between HuR as repressor of alternative Fas splicing and the molecular mechanisms modulating programmed cell death.
Izquierdo
José M
JM
Departamento de Biología Molecular and the Centro de Biología Molecular Severo Ochoa, C.S.I.C., Universidad Autónoma de Madrid, Cantoblanco 28049, Madrid, Spain. jmizquierdo@cbm.uam.es
D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D004331:Drosophila melanogaster; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D005091:Exons / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D039102:Poly(A)-Binding Proteins / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism*; D022821:RNA Splice Sites / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000235:genetics / Q000378:metabolism; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics / Q000378:metabolism; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism; D012262:Ribonucleoside Diphosphate Reductase; D000072668:Splicing Factor U2AF; D000074019:T-Cell Intracellular Antigen-1; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D019014:fas Receptor
D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D009687:Nuclear Proteins; D039102:Poly(A)-Binding Proteins; D012322:RNA Precursors; D022821:RNA Splice Sites; D016601:RNA-Binding Proteins; D017412:Ribonucleoprotein, U1 Small Nuclear; D017413:Ribonucleoprotein, U2 Small Nuclear; D012261:Ribonucleoproteins; D000072668:Splicing Factor U2AF; D000074019:T-Cell Intracellular Antigen-1; C071558:TIA1 protein, human; D025521:Tumor Suppressor Proteins; C000607494:U2AF2 protein, human; D019014:fas Receptor; C076751:TIAL1 protein, human; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase