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J. Biol. Chem., Vol. 279, Issue 53, 55594-55601, December 31, 2004

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Fas-associated Protein with Death Domain (FADD)-independent Recruitment of c-FLIP_L to Death Receptor 5^*

Tai-Guang Jin, Alexei Kurakin¶, Nordine Benhaga||, Karon Abe||, Mehrdad Mohseni, Ferry Sandra, Keli Song, Brian K. Kay**, and Roya Khosravi-Far

From the Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, the ^¶Buck Institute for Age Research, Novato, California 94945, and the ^**Argonne National Laboratory, Argonne, Illinois 60439

Here we show a novel mechanism by which FLICE-like inhibitory protein (c-FLIP) regulates apoptosis induced by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and one of its receptors, DR5. c-FLIP is a critical regulator of the TNF family of cytokine receptor signaling. c-FLIP has been postulated to prevent formation of the competent death-inducing signaling complex (DISC) in a ligand-dependent manner, through its interaction with FADD and/or caspase-8. In order to identify regulators of TRAIL function, we used the intracellular death domain (DD) of DR5 as a target to screen a phage-displayed combinatorial peptide library. The DD of DR5 selected from the library a peptide that showed sequence similarity to a stretch of amino acids in the C terminus of c-FLIP_L. The phage-displayed peptide selectively interacted with the DD of DR5 in in vitro binding assays. Similarly, full-length c-FLIP (c-FLIP_L) and the C-terminal p12 domain of c-FLIP interacted with DR5 both in in vitro pull-down assays and in mammalian cells. This interaction was independent of TRAIL. To the contrary, TRAIL treatment released c-FLIP_L from DR5, permitting the recruitment of FADD to the active DR5 signaling complex. By employing FADD-deficient Jurkat cells, we demonstrate that DR5 and c-FLIP_L interact in a FADD-independent manner. Moreover, we show that a cellular membrane permeable version of the peptide corresponding to the DR5 binding domain of c-FLIP induces apoptosis in mammalian cells. Taken together, these findings indicate that c-FLIP interacts with the DD of DR5, thus preventing death ^Lsignaling by DR5 prior to the formation of an active DISC. Because TRAIL and DR5 are ubiquitously expressed, the interaction of c-FLIP_L and DR5 indicates a mechanism by which tumor selective apoptosis can be achieved through protecting normal cells from undergoing death receptor-induced apoptosis.

Received for publication, January 30, 2004 , and in revised form, October 1, 2004.

^* This study was supported by Public Health Service Grants 1 R55 CA87675 and HL080192 from the National Institutes of Health, DAMD 17-02-0299 from the Department of Defense, and RSG 03-012-01-CCG from the American Cancer Society (to R. K.-F.). 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.

These authors made key independent contributions.

^|| Supported by Grant T32 H07893 from National Institutes of Health.

To whom correspondence should be addressed: Dept. of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Ave, RN 270F, Boston, MA 02215. Tel.: 617-667-8526; Fax: 617-667-3524; E-mail: rkhosrav{at}bidmc.harvard.edu.

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