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Molecular and Cellular Biology, August 2004, p. 7214-7224, Vol. 24, No. 16
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.16.7214-7224.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Vanin-1–/– Mice Exhibit a Glutathione-Mediated Tissue Resistance to Oxidative Stress

C. Berruyer,1,{dagger} F. M. Martin,1,{dagger},{ddagger} R. Castellano,1 A. Macone,2 F. Malergue,1 S. Garrido-Urbani,1 V. Millet,1 J. Imbert,3 S. Duprè,2 G. Pitari,4 P. Naquet,1 and F. Galland1*

Centre d'Immunologie de Marseille-Luminy CNRS-INSERM-Université de la Méditerranée, 13288 Marseille,1 INSERM U599, 13009 Marseille, France,3 Dipartimento di Scienze Biochimiche "A. Rossi Fanelli," Instituto di Biologia e Patologia Molecolari del CNR, Università di Roma "La Sapienza," 00185 Rome,2 Dipartimento di Biologia di Base ed Applicata, Università di L'Aquila, Coppito L'Aquila, Italy4

Received 6 January 2004/ Returned for modification 9 February 2004/ Accepted 6 May 2004

Vanin-1 is an epithelial ectoenzyme with pantetheinase activity and generating the amino-thiol cysteamine through the metabolism of pantothenic acid (vitamin B5). Here we show that Vanin-1–/– mice, which lack cysteamine in tissues, exhibit resistance to oxidative injury induced by whole-body {gamma}-irradiation or paraquat. This protection is correlated with reduced apoptosis and inflammation and is reversed by treating mutant animals with cystamine. The better tolerance of the Vanin-1–/– mice is associated with an enhanced gamma-glutamylcysteine synthetase activity in liver, probably due to the absence of cysteamine and leading to elevated stores of glutathione (GSH), the most potent cellular antioxidant. Consequently, Vanin-1–/– mice maintain a more reducing environment in tissue after exposure to irradiation. In normal mice, we found a stress-induced biphasic expression of Vanin-1 regulated via antioxidant response elements in its promoter region. This process should finely tune the redox environment and thus change an early inflammatory process into a late tissue repair process. We propose Vanin-1 as a key molecule to regulate the GSH-dependent response to oxidative injury in tissue at the epithelial level. Therefore, Vanin/pantetheinase inhibitors could be useful for treatment of damage due to irradiation and pro-oxidant inducers.

* Corresponding author. Mailing address: Centre d'Immunologie de Marseille-Luminy CNRS-INSERM-Université de la Méditerranée, Parc scientifique de Luminy, case 906, cedex 9, 13288 Marseille, France. Phone: (33) 4 91 26 94 97. Fax: (33) 4 91 26 94 30. E-mail: galland{at}ciml.univ-mrs.fr.

{dagger} C.B. and F.M.M. contributed equally to this work.

{ddagger} Present address: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037.

Molecular and Cellular Biology, August 2004, p. 7214-7224, Vol. 24, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.16.7214-7224.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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