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J. Biol. Chem., Vol. 281, Issue 19, 13663-13671, May 12, 2006

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The Stability and Anti-apoptotic Function of A1 Are Controlled by Its C Terminus^*

From the Institute for Virology and Immunobiology, University of Würzburg, Versbacher Strasse 7, 97078 Würzburg, Germany

Most Bcl-2 family members can localize to intracellular membranes via hydrophobic sequences within their C-terminal portion. We found that the C terminus of the anti-apoptotic family member A1 did not function as a membrane anchor. Instead, this stretch of the protein rendered A1 highly unstable by mediating its polyubiquitination and rapid proteasomal degradation. Moreover, the domain did not only function independently of its position within the A1 protein but when transfered could even destabilize unrelated proteins like enhanced green fluorescent protein and caspase-3. A1 was, however, much more stable in the presence of the Bcl-2 homology-only protein BimEL, suggesting that direct interaction of A1 with pro-apoptotic members of the Bcl-2 family strongly reduces its rate of turnover. We further show that the C-terminal end of A1 also contributes to the anti-apoptotic capacity of the protein. In conclusion, our data demonstrate that the C terminus serves a dual function by controlling the stability of A1 and by amplifying the capacity of the protein to protect cells against apoptosis.

Received for publication, January 10, 2006 , and in revised form, March 13, 2006.

^* This work was supported by Wilhelm Sander-Stiftung (1999.107.2) and the Graduate College Immunomodulation Grant GK520/2. 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 Both authors contributed equally to this work.

² Present address: Dept. of Biology/Immunology, University of Konstanz, Universitätsstrasse 10, 78457 Konstanz, Germany.

³ To whom correspondence should be addressed: Institute for Virology and Immunobiology, University of Würzburg, Versbacher Strasse 7, 97078 Würzburg, Germany. Tel.: 49-931-201-49930; Fax: 49-931-201-49243, E-mail: berberich.i{at}uni-wuerzburg.de.

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