Glyceraldehyde-3-phosphate dehydrogenase regulates endothelin-1 expression by a novel, redox-sensitive mechanism involving mRNA stability.
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.
Rodríguez-Pascual
Fernando
F
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Instituto Reina Sofía de Investigaciones Nefrológicas, Madrid, Spain. frodriguez@cib.csic.es
Redondo-Horcajo
Mariano
M
Magán-Marchal
Noemi
N
Lagares
David
D
Martínez-Ruiz
Antonio
A
Kleinert
Hartmut
H
Lamas
Santiago
S
D020413:3' Untranslated Regions; D019332:Endothelin-1 / Q000235:genetics*; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011485:Protein Binding; D020871:RNA Stability; D014471:Umbilical Veins / Q000166:cytology
D020413:3' Untranslated Regions; D019332:Endothelin-1; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D005978:Glutathione