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J. Biol. Chem., Vol. 283, Issue 27, 19077-19084, July 4, 2008

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Hu Antigen R (HuR) Functions as an Alternative Pre-mRNA Splicing Regulator of Fas Apoptosis-promoting Receptor on Exon Definition^*

From the Departamento de Biología Molecular and the Centro de Biología Molecular "Severo Ochoa," C.S.I.C., Universidad Autónoma de Madrid, Cantoblanco 28049, Madrid, Spain

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.

Received for publication, January 2, 2008 , and in revised form, March 27, 2008.

^* This work was supported by a grant from Fondo de Investigaciones Sanitarias (PI051605). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Departamento de Biología Molecular, Centro de Biología Molecular "Severo Ochoa", Universidad Autónoma de Madrid, Consejo Superior de Investigaciones Científicas, Cantoblanco 28049, Madrid, Spain. Tel.: 34-91-1964530; Fax: 34-91-1964420; E-mail: jmizquierdo{at}cbm.uam.es.

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