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J. Biol. Chem., Vol. 281, Issue 27, 18507-18518, July 7, 2006

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Identification and Characterization of AIFsh2, a Mitochondrial Apoptosis-inducing Factor (AIF) Isoform with NADH Oxidase Activity^*

From the Apoptose et Système Immunitaire, CNRS-URA 1961, Institut Pasteur, 25 rue du Dr. Roux, 75015 Paris, France

Apoptosis-inducing factor (AIF) is a bifunctional NADH oxidase involved in mitochondrial respiration and caspase-independent apoptosis. Three alternatively spliced mRNA isoforms of AIF have been identified previously: AIF, AIF-exB, and AIFsh. Here, we report the cloning and the biochemical characterization of a new isoform named AIF short 2 (AIFsh2). AIFsh2 transcript includes a previously unknown exon placed between exons 9 and 10 of AIF. The resulting AIFsh2 protein, which localizes in mitochondria, corresponds to the oxidoreductase domain of AIF. In this way, AIFsh2 exhibits similar NADH oxidase activity to AIF and generates reactive oxygen species. Like AIF, AIFsh2 is released from mitochondria to cytosol after an apoptotic insult in a calpain or cathepsin-dependent manner. However, in contrast to AIF, AIFsh2 does not induce nuclear apoptosis. Thus, it seems that the reactive oxygen species produced by the oxidoreductase domain of AIF/AIFsh2 are not important for AIF-dependent nuclear apoptosis. In addition, we demonstrate that the AIFsh2 mRNA is absent in normal brain tissue, whereas it is expressed in neuroblastoma-derived cells, suggesting a different regulation in normal and transformed cells from the brain lineage. Together, our results reveal that AIF yields an original and independent genetic regulation of the two AIF functions. This is an important issue to understand the physiological role of this protein.

Received for publication, February 23, 2006 , and in revised form, April 26, 2006.

^* This work was supported in part by grants from Fondation de France and Association pour la Recherche sur le Cancer contract number 4812. 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.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) DQ016498, DQ016500, and DQ016499 for the human AIFsh2, AIFsh3 and mAIFsh2, respectively.

¹ Supported by a postdoctoral fellowship from Fondation de France.

² Supported by a Marie Curie Intra-European fellowship within the 6^th European Community Framework Programme under contract MEIF-2003-501887.

³ Supported by a Ph.D. fellowship from the Fondation Hariri.

⁴ Supported by a Ph.D. fellowship from Caisse Nationale d'Assurance Maladie des Professions Indépendantes (CANAM)-Pasteur.

⁵ To whom correspondence should be addressed: Apoptose et Systeme Immunitaire, Institut Pasteur, 25 rue du Dr. Roux, 75015 Paris, France. Tel.: 33-1-40-61-31-84; Fax: 33-1-40-61-31-86; E-mail: susin{at}pasteur.fr.

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