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Molecular and Cellular Biology, December 2008, p. 7139-7155, Vol. 28, No. 23
0270-7306/08/$08.00+0     doi:10.1128/MCB.01145-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Glyceraldehyde-3-Phosphate Dehydrogenase Regulates Endothelin-1 Expression by a Novel, Redox-Sensitive Mechanism Involving mRNA Stability{triangledown}

Fernando Rodríguez-Pascual,1* Mariano Redondo-Horcajo,1 Noemi Magán-Marchal,1 David Lagares,1 Antonio Martínez-Ruiz,2 Hartmut Kleinert,3 and Santiago Lamas1*

Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Instituto Reina Sofía de Investigaciones Nefrológicas, E-28040 Madrid, Spain,1 Servicio de Inmunología, Hospital de la Princesa, E-28006 Madrid, Spain,2 Department of Pharmacology, Johannes Gutenberg University, D-55101 Mainz, Germany3

Received 21 July 2008/ Returned for modification 12 August 2008/ Accepted 12 September 2008

The regulation of the synthesis of the endothelial-derived vasoconstrictor endothelin-1 (ET-1) is a complex process encompassing transcriptional as well as mRNA stability mechanisms. We have described recently the existence of a mechanism for the control of ET-1 expression based on the mRNA-destabilizing capacity of specific cytosolic proteins through interaction with AU-rich elements (AREs) present in the 3' untranslated region of the gene. We now identify glyceraldehyde-3'-phosphate dehydrogenase (GAPDH) as a protein which binds to the AREs and is responsible for the destabilization of the mRNA. Oxidant stress alters the binding of GAPDH to the mRNA and its capacity to modulate ET-1 expression, a phenomenon occurring through specific S glutathionylation of the catalytically active residue Cys 152. Finally, we provide data consistent with a role for GAPDH in mRNA unwinding, yielding this molecule more prone to degradation. In contrast, S-thiolated GAPDH appears unable to modify mRNA unwinding, thus facilitating enhanced stability. Taken together, these results describe a novel, redox-based mechanism regulating mRNA stability and add a new facet to the panoply of GAPDH cellular homeostatic actions.

* Corresponding author. Mailing address: Centro de Investigaciones Biológicas, Ramiro de Maeztu 9, E-28040 Madrid, Spain. Phone: 34 91 837 31 12, ext. 4419. Fax: 34 91 536 04 32. E-mail for Fernando Rodríguez-Pascual: frodriguez{at}cib.csic.es. E-mail for Santiago Lamas: slamas{at}cib.csic.es

{triangledown} Published ahead of print on 22 September 2008.

Molecular and Cellular Biology, December 2008, p. 7139-7155, Vol. 28, No. 23
0270-7306/08/$08.00+0     doi:10.1128/MCB.01145-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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