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J. Biol. Chem., Vol. 280, Issue 29, 27345-27355, July 22, 2005

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Rapid Turnover of c-FLIPshort Is Determined by Its Unique C-terminal Tail^*

Minna Poukkula¶, Aura Kaunisto, Ville Hietakangas¶||, Konstantin Denessiouk**, Tuire Katajamäki**, Mark S. Johnson**, Lea Sistonen||, and John E. Eriksson

From the Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, FIN-20521 Turku, the Department of Biology, University of Turku, FIN-20014 Turku, and the Departments of ^||Biology and ^**Biochemistry and Pharmacy, Åbo Akademi University, FIN-20520 Turku, Finland

The caspase-8 inhibitor c-FLIP exists as two splice variants, c-FLIP_L and c-FLIP_S, with distinct roles in death receptor signaling. The mechanisms determining their turnover have not been established. We found that in differentiating K562 erythroleukemia cells both c-FLIP isoforms were inducibly degraded by the proteasome, but c-FLIP_S was more prone to ubiquitylation and had a considerably shorter half-life. Analysis of the c-FLIP_S-specific ubiquitylation revealed two lysines, 192 and 195, C-terminal to the death effector domains, as principal ubiquitin acceptors in c-FLIP_S but not in c-FLIP_L. Furthermore the c-FLIP_S-specific tail of 19 amino acids, adjacent to the two target lysines, was demonstrated to be the key element determining the isoform-specific instability of c-FLIP_S. Molecular modeling in combination with site-directed mutagenesis demonstrated that the C-terminal tail is required for correct positioning and subsequent ubiquitylation of the target lysines. Because the antiapoptotic operation of c-FLIP_S was not affected by the tail deletion, the antiapoptotic activity and ubiquitin-mediated degradation of c-FLIP_S are functionally and structurally independent processes. The presence of a small destabilizing sequence in c-FLIP_S constitutes an important determinant of c-FLIP_S/c-FLIP_L ratios by allowing differential degradation of c-FLIP isoforms. The conformation-based predisposition of c-FLIP_S to ubiquitin-mediated degradation introduces a novel concept to the regulation of the death-inducing signaling complex.

Received for publication, April 13, 2005 , and in revised form, May 10, 2005.

^* This work was supported by the Academy of Finland, the Association of the Finnish Life Insurance Companies, the Sigrid Jusélius Foundation, the Finnish Cancer Organizations, the Paulo Foundation, the Ida Montin Foundation, and the Finnish Cultural Foundation. 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.

^¶ Supported by the Turku Graduate School of Biomedical Sciences (TuBS).

To whom correspondence should be addressed: Turku Centre for Biotechnology, P. O. Box 123, FIN-20521 Turku, Finland. Tel.: 358-2-333-8036; Fax: 358-2-333-8000; E-mail: john.eriksson{at}utu.fi.

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