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Nuclear Factor- B-Inducible Death Effector Domain-Containing Protein

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Nuclear Factor- B-Inducible Death Effector Domain-Containing Protein THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 276, No. 28, Issue of July 13, pp. 26398–26404, 2001 © 2001 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in U.S.A. Nuclear Factor-␬B-inducible Death Effector Domain-containing Protein Suppresses Tumor Necrosis Factor-mediated Apoptosis by Inhibiting Caspase-8 Activity* Received for publication, March 19, 2001, and in revised form, May 8, 2001 Published, JBC Papers in Press, May 9, 2001, DOI 10.1074/jbc.M102464200 Zongbing You‡, Hongjiao Ouyang‡§, Dennis Lopatin¶, Peter J. Polverʈ, and Cun-Yu Wang‡** From the ‡Laboratory of Molecular Signaling and Apoptosis, the Department of Biologic and Materials Sciences, School of Dentistry, Program in Cellular and Molecular Biology, and Comprehensive Cancer Center, the §Department of Cardiology, Restorative Sciences and Endodontics, and the ¶Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, Michigan 48109 and the ʈSchool of Dentistry, University of Minnesota, Minneapolis, Minnesota 55455 Activation of the transcription factor nuclear fac- ing pathway or trigger the caspase cascade by interacting with tor-␬B (NF-␬B) has been found to play an essential role FADD (Fas-associated death domain protein) in the absence of in the inhibition of tumor necrosis factor (TNF)-medi- NF-␬B activation (1–3). FADD recruits and activates ated apoptosis. NF-␬B regulates several antiapoptotic caspase-8. Both caspase-8 and FADD contain death effector molecules including inhibitors of apoptosis, Bcl-2 family domains (DED) that were found to play a critical role for the proteins (A1 and Bcl-XL), and IEX-IL. Here we report protein-protein interaction and caspase activation (4, 5). Active that the expression of a small death effector domain caspase-8 promotes cell death by cleaving the cytosolic Bid ␬ (DED)-containing protein, NDED (NF- B-inducible protein, a proapoptotic family member of Bcl-2 (6, 7). Trun- DED-containing protein), depends on the activation of cated Bid translocates to mitochondria, resulting in the release NF-␬B. The inhibition of NF-␬BbyI␬B␣, a natural inhib- of cytochrome c from mitochondria to the cytosol (6–8). Cyto- itor of NF-␬B, suppressed NDED mRNA expression in- duced by TNF. The restoration of NDED in NF-␬B null chrome c, along with ATP and Apaf-1, a mammalian homologue cells inhibited TNF-induced apoptosis. Intriguingly, un- of Ced-4, recruits and activates procaspase-9. The active like the caspase-8 inhibitor cellular FADD-like interleu- caspase-9 amplifies apoptosis by the cleavage of downstream kin-1␤ converting enzyme-inhibitory protein (c-FLIP), effector caspases (9–11). Although biochemical and genetic NDED suppressed TNF-mediated apoptosis by inhibit- studies have indicated that Bid plays an important role in ing TNF-induced caspase-8 enzymatic activity but not promoting death receptor-mediated apoptosis (6–8), it is not the processing of caspase-8. Furthermore, NDED could known whether the cleavage of Bid is modulated by antiapo- not inhibit etoposide-mediated apoptosis that is inde- ptotic molecules. pendent of caspase-8 activation. Our results provide the NF-␬B is a stress-responsive transcription factor that plays first demonstration that NF-␬B transcriptionally in- important roles in inflammation and infection (2, 12, 13). Clas- duces the DED-containing protein to suppress TNF-me- sical NF-␬B is a heterodimer composed of p50 and p65/RelA diated apoptosis by inhibiting caspase-8 activity, which and is sequestered in the cytoplasm by the I␬B group of inhib- offers new insight into the antiapoptotic mechanism of itory proteins. Proinflammatory cytokines such as TNF acti- NF-␬B. vate I␬B kinase to phosphorylate the conserved N-terminal region of I␬B proteins. The phosphorylated I␬B is ubiquitinated and subsequently degraded by the 26S proteasome, resulting in Activation of the TNF1 receptor I (TNFRI) by TNF leads to the nuclear translocation of NF-␬B where it activates tran- the recruitment of the death domain-containing protein TN- scription (2, 12, 13). Recently, we and others (14–19) demon- FRI-associated death domain protein and receptor-interacting strated that NF-␬B plays an essential role in inhibiting TNF- protein to the receptor complex (1, 2). Along with the receptor- mediated apoptosis. Several important antiapoptotic molecules interacting protein and other signaling molecules, TNFRI-as- have been identified that are transcriptionally regulated by sociated death domain protein can activate the NF-␬B signal- NF-␬B. These molecules include inhibitors of apoptosis family proteins, TNFR-associated factor family proteins, Bcl-2 family members A1 and Bcl-X , and IEX-1L (20–25). However, over- * This work was supported by National Institutes of Health Research L Grant R01-DE13848 and R01-DE13788 (to C.-Y. W.). The costs of pub- expression of these molecules cannot completely inhibit TNF- lication of this article were defrayed in part by the payment of page induced apoptosis, indicating that NF-␬B may regulate other charges. This article must therefore be hereby marked “advertisement” genes to suppress apoptosis. in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. During the process of searching for other NF-␬B-inducible ** To whom correspondence should be addressed: Laboratory of Mo- lecular Signaling and Apoptosis, Dept. of Biologic and Materials Sci- genes, we found that one of the TNF-induced genes, previously ences, University of Michigan, 1011 N. University Ave., Ann Arbor, MI named GG2–1 (27) or SCC-S2 (28), was transcriptionally reg- 48109-1078. Tel.: 734-615-4386; Fax: 734-764-2425; E-mail: ulated by NF-␬B. Interestingly, this gene has one DED domain [email protected]. and partially inhibits TNF killing by unknown mechanisms 1 The abbreviations used are: TNF, tumor necrosis factor; TNFRI, TNF receptor I; NF-␬B, nuclear factor-␬B; FADD, Fas-associated death (28). Because we found that GG2–1 or SCC-S2 was regulated domain protein; DED, death effector domain; NDED, NF-␬B-inducible by NF-␬B as presented here, for convenience we renamed it DED-containing protein; SSC, squamous cell carcinoma cells; I␬B␣, NDED (NF-␬B-inducible death effector domain-containing pro- ␣ ␬ ␣ ␬ ␣ inhibitor of kappa B ; SR-I B , super-repressor form of I B ; c-FLIP, tein). Given that the DED-containing protein plays a role in the cellular FADD-like interleukin-1␤ converting enzyme-inhibitory pro- tein; DFF, DNA fragmentation factor; DISC, death-inducing signaling death signal transduction (1–3), this study was undertaken to complex. determine whether NDED is an authentic NF-␬B-regulated 26398 This paper is available on line at http://www.jbc.org NDED Inhibits TNF-mediated Apoptosis 26399 FIG.1.NDED expression is induced by TNF through the acti- vation of NF-␬B in squamous cell carcinoma. A, TNF-induced nuclear translocation of NF-␬B is inhibited by adenovirus-mediated delivery of SR-I␬B␣. The cells were infected with adenovirus-expressing SR-I␬B␣ or control virus at a multiplicity of infection of 1:500. Twenty- four h after infection, the cells were treated with TNF for the indicated time, and the nuclear extracts were prepared. Five ␮g of proteins were used for the electrophoretic mobility shift assay as described under “Experimental Procedures.” B, the induction of NDED expression by FIG.3.NDED expression in NF-␬B null cells partially inhibits TNF depends on the activation of NF-␬B. Adenovirus infection was TNF-mediated apoptosis. A, the establishment of HT1080I cells sta- performed as described for A. Twenty-four h after infection, the cells bly expressing NDED. HT1080I cells were co-transfected with pCMV2- were treated with TNF for the indicated time. For the prevention of FLAG-NDED vector or control empty vector pcDNA3.1 (Ϫ) using Lipo- apoptosis, cells were pretreated with caspase inhibitor Z-VAD at a fectAMINE. Twenty-four h after transfection, the cells were selected concentration of 20 ␮M for 30 min before TNF stimulation. Total RNA with G418 (600 ␮g/ml) for 2 weeks. About 50 clones were screened by was extracted with Trizol reagent and 20 ␮g of RNA were used for monoclonal antibody against the FLAG epitope. Six positive clones that Northern blot analysis. The membrane was probed with a 32P-labeled expressed similar levels of NDED protein were pooled (HT1080I-N). human NDED cDNA probe. For loading control, the blot was stripped Lane 1 represents control cells (HT1080I-C) expressing the G418-re- and reprobed with 32P-labeled GAPDH cDNA probe. TNF stimulation of sistant marker; lanes 2 and 3 represent HT1080I cells stably expressing NDED mRNA expression was quantified using a PhosphorImager and FLAG-NDED. B and C, NDED inhibited cell killing by TNF. Cells were normalized with GAPDH. The fold inductions were expressed as ratios treated with the indicated concentrations of TNF for8h(B) and with of radioactivities in treated and untreated cells. TNF (5 ng/ml) for the indicated time periods (C). The detached and attached cells were collected, and the dead cells were determined by the trypan blue exclusion assay. The assays were performed in triplicate, and the result represents the average values from three independent experiments. Statistical differences between each group were deter- mined by the Student’s t test. *, p Ͻ 0.01. but not the processing of caspase-8, subsequently resulting in inhibition of Bid cleavage and caspase-3 activation. EXPERIMENTAL PROCEDURES Cell Culture—Human head and neck squamous cell carcinoma cells SCC15 (ATCC) were cultured in Dulbecco’s modified Eagle’s medium supplemented with 10% fetal calf serum, 100 ␮g/ml penicillin, and 100 ␬ FIG.2.NDED expression depends on the activation of NF- B ␮g/ml streptomycin. Human fibrosarcoma cells HT1080V and HT1080I in HT1080 fibrosarcoma cells. HT1080V and HT1080I cells were cells were cultured in Eagle’s minimal essential medium supplemented treated with TNF for the indicated times.
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