The Adaptor TRADD Is Essential for TNF-Like 1A/Death 3 Signaling

This information is current as Yelena L. Pobezinskaya, Swati Choksi, Michael J. Morgan, of September 26, 2021. Xiumei Cao and Zheng-gang Liu J Immunol 2011; 186:5212-5216; Prepublished online 18 March 2011; doi: 10.4049/jimmunol.1002374

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Supplementary http://www.jimmunol.org/content/suppl/2011/03/18/jimmunol.100237 Material 4.DC1 http://www.jimmunol.org/ References This article cites 29 articles, 13 of which you can access for free at: http://www.jimmunol.org/content/186/9/5212.full#ref-list-1

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The Adaptor Protein TRADD Is Essential for TNF-Like Ligand 1A/ Signaling

Yelena L. Pobezinskaya, Swati Choksi, Michael J. Morgan, Xiumei Cao, and Zheng-gang Liu

TNFR-associated protein (TRADD) is a key effector protein of TNFR1 signaling. However, the role of TRADD in other death receptor (DR) signaling pathways, including DR3, has not been completely characterized. Previous studies using over- expression systems suggested that TRADD is recruited to the DR3 complex in response to the DR3 ligand, TNF-like ligand 1A (TL1A), indicating a possible role in DR3 signaling. Using T cells from TRADD knockout mice, we demonstrate in this study that the response of both CD4+ and CD8+ T cells to TL1A is dependent upon the presence of TRADD. TRADD knockout T cells therefore lack the appropriate proliferative response to TL1A. Moreover, in the absence of TRADD, both the stimulation of

MAPK signaling and activation of NF-kB in response to TL1A are dramatically reduced. Unsurprisingly, TRADD is required for Downloaded from recruitment of receptor interacting protein 1 and TNFR-associated factor 2 to the DR3 signaling complex and for the ubiquiti- nation of receptor interacting protein 1. Thus, our findings definitively establish an essential role of TRADD in DR3 signaling. The Journal of Immunology, 2011, 186: 5212–5216.

eath receptor (DR) 3 (also known as TNFRSF25, WSL-1, vation of MAPK and NF-kB. In some cases, a secondary complex http://www.jimmunol.org/ LARD, TRAMP, Apo3) is a member of the TNFR su- (complex II) dissociates from the receptor and associates with D perfamily and a member of the DR subfamily that has FADD (14), and this complex is responsible for activation seven additional members, including TNFR1, FAS, DR4, DR5, and . This is in contrast to other death receptors, such as DR6, nerve growth factor receptor, and ectodysplasin 1 anhidrotic Fas, DR4, and DR5, which are capable of binding directly to receptor (1). All of the receptors of this subfamily contain a death FADD in the primary receptor complex (1). The generation of domain (DD) as a part of their intracellular domain, and of these RIP1 and TRAF2 knockout mice did much to unveil the important seven, DR3 has the highest homology to TNFR1 (2–5). However, functions of these molecules in MAPK and NF-kB activation in contrast to the ubiquitous expression of TNFR1, DR3 expres- downstream of TNFR1 (15, 16). However, TRADD has always sion is restricted to lymphocyte-enriched tissues such as thymus, been considered to be the first adaptor molecule that is recruited to by guest on September 26, 2021 spleen, small intestine, and PBL (2–6) and has been shown to be TNFR1 (17), and TRADD-deficient mice generated recently by especially upregulated in activated T cells (5, 6). The ligand to our laboratory (18) and others (19, 20) made it possible to de- DR3 receptor is a member of the TNF superfamily and is called finitively establish the role of TRADD in TNFR1 signaling that TNF-like ligand 1A (TL1A or TNFSF15). Originally thought to occurs mainly through recruitment of these molecules. be predominantly expressed by endothelial cells (7), later studies A majority of studies on the mechanisms of DR3 signaling have have shown that TL1A can be produced by variety of other cells been conducted previously using overexpression systems. Similar including monocytes, macrophages, plasma cells, dendritic cells, to TNFR1, DR3 induces both NF-kB activation and apoptosis and T cells (8–10). when ectopically overexpressed in cell lines (2–5). Of the adaptor TNFR1 signaling has been very well characterized. The TNF- tested in overexpression studies, TRADD was the only a–dependent activation of TNFR1 leads to formation of a signal- protein that had a strong interaction directly with DR3 (2, 4), ing complex that contains several important molecules, includ- whereas the association of RIP and TRAF2 with DR3 was very ing TNFR-associated death domain protein (TRADD), receptor weak and greatly enhanced in the presence of transfected TRADD interacting protein (RIP), and TNFR-associated factor (TRAF) 2 (4). In these systems, FADD was also shown to be recruited to (11–13). These molecules are responsible for mediating the acti- DR3 upon coexpression of TRADD, and association of FADD directly with DR3 was observed only at very high expression levels (3). In addition, DR3-mediated apoptosis was dependent on Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer In- the presence of FADD and caspase-8 in embryonic mouse fibro- stitute, National Institutes of Health, Bethesda, MD 20892 blasts (15, 21). These studies do suggest that TRADD is the pri- Received for publication July 14, 2010. Accepted for publication February 18, 2011. mary adaptor recruited to DR3 upon TL1A stimulation. However, This work was supported by the Intramural Research Program of the Center for a detailed examination of the physiological role of TRADD in Cancer Research, National Cancer Institute, National Institutes of Health. DR3 signaling pathways has not yet been undertaken. Address correspondence and reprint requests to Dr. Zheng-gang Liu, Cell and Cancer Biology Branch, National Cancer Institute, National Institutes of Health, Building 37, We therefore sought to examine DR3 signaling events in cells Room 1130, 37 Convent Drive, Bethesda, MD 20892. E-mail address: zgliu@helix. derived from TRADD knockout mice. In this study, we show that in nih.gov the absence of TRADD, TL1A cannot induce proper JNK and NF- The online version of this article contains supplemental material. kB activation. This is largely due to the inability of DR3 to effect Abbreviations used in this article: cIAP2, cellular 2; DD, death the recruitment of the critical adaptor proteins TRAF2 and RIP1 domain; DR, death receptor; RIP, receptor interacting protein; TL1A, TNF-like li- gand 1A; TRADD, TNFR-associated death domain protein; TRAF, TNFR-associated in TRADD-deficient cells, thus leading to a nonfunctional DR3 factor. signaling complex. Moreover, TL1A does not promote T cell pro- www.jimmunol.org/cgi/doi/10.4049/jimmunol.1002374 The Journal of Immunology 5213 liferation in TRADD-deficient cells. We also confirm that TL1A- proliferation and cytokine production of T cells stimulated induced DR3 signaling does not result in T cell apoptosis. through the TCR (23). We therefore sought to determine whether TRADD was important for these events. CD4+ and CD8+ T cells Materials and Methods were purified from lymph nodes of wild-type and TRADD2/2 Reagents mice and labeled with CFSE. Because TL1A increases T cell proliferation better when the CD28 costimulatory signal is absent Anti–phospho-JNK Ab was purchased from Biosource International. Anti- TRADD and TRAF2 Abs were purchased from Santa Cruz Biotechnology. (23), we preactivated T cells with anti-CD3 only and treated with Anti-JNK, RIP, Fas, CD28, CD3ε, anti-CD4–PE, and anti-CD8–allophyco- TL1A or IL-2 for 72 h. In contrast to wild-type T cells, which cyanin Abs were from BD Pharmingen. Anti–phospho-IkBa, anti–phospho- proliferated very well in response to TL1A (as seen by the dilution p38, anti-p38, anti–phospho-ERK, and anti-ERK were purchased from Cell peaks on the CFSE histogram), CD4+ TRADD-deficient T cells Signaling Technology. Recombinant murine TL1A, TNF-a, IL-2, and anti- showed very minimal proliferation (Fig. 1A). Similar differences DR3 Ab were from R&D Systems. PMA was from Alexis Biochemicals. + SMAC mimetic (SM-164) was a kind gift from Dr. Shaomeng Wang. were seen in the CD8 T cells (Fig. 1B). However, IL-2–induced proliferation was minimally affected by the absence of TRADD in Animals either CD4+ or CD8+ T cells, suggesting that the defect in the TRADD knockout mice were described previously (18). Three- to 4-wk-old proliferative response was specific for TL1A treatment. TRADD knockout and wild-type littermates were used to isolate T cells. Next we sought to determine whether the lack of proliferation T cell purification was due to a deficiency in the downstream signaling pathways and

+ + whether TRADD has a role in DR3-mediated MAPK signaling and Purification of CD4 and CD8 lymph node T cells or pan T cells was NF-kB activation. We examined phosphorylation of JNK and Downloaded from performed using MACS CD4+ and CD8+ T cell or pan T cell isolation kits (Miltenyi Biotec), respectively, according to the manufacturer’s instruc- tions. Briefly, lymph node cell populations were depleted of non-T cells by incubation with biotin-conjugated Ab mixture and antibiotin magnetic microbeads followed by separation on MACS columns. Purity of isolated T cells was .97%.

Treatment of cells http://www.jimmunol.org/ Before any treatment, T cells were preactivated with plate-bound anti-CD3 (1 mg/ml) Abs overnight. In vitro cell proliferation assay T cells were washed with PBS twice, resuspended at 106/ml in PBS, warmed in 37˚C water bath for 10 min, mixed with 1 ml 5 mM CFSE stock (Vybrant CFDA SE cell tracer kit; Molecular Probes Invitrogen), and in- cubated in 37˚C water bath for 10 min. Reaction was stopped with ice-cold complete RPMI 1640 media. Cells were then plated in 24-well plates at 0.5 3 106/well, harvested after 72 h, stained with anti-CD4 or CD8 Ab, by guest on September 26, 2021 and analyzed on an FACSCalibur (BD Biosciences) using FlowJo software (Tree Star). Western blot analysis and coimmunoprecipitation After treatments as described in the figure legends, cells were collected and lysed in M2 buffer (20 mM Tris [pH 7], 0.5% Nonidet-P40, 250 mM NaCl, 3 mM EDTA, 3 mM EGTA, 2 mM DTT, 0.5 mM PMSF, 20 mM b-glycerol phosphate, 1 mM sodium vanadate, and 1 mg/ml leupeptin). Cell lysates were fractionated by SDS-polyacrylamide gel and Western blotted. The proteins were visualized by ECL according to the manufacturer’s in- struction (Amersham Biosciences). For immunoprecipitation assays, cells were treated with TL1A as indicated in the figure legends and then col- lected in lysis M2 buffer. The lysates were mixed and precipitated with anti-DR3 Abs (R&D Systems) and protein G-Agarose beads by incubation at 4˚C for overnight. The beads were washed five times with lysis buffer, and the bound proteins were resolved in 4–20% SDS-polyacrylamide gels and detected by Western blot analysis. EMSA Nuclear extracts were isolated using the Biovision Nuclear/Cytosol frac- tionation kit following the manufacturer’s guidelines (Biovision). Gel shifts were performed with the Promega Gel shift assay system (Promega) using 10 mg nuclear extract and following the recommendations outlined in the manufacturer’s protocol. All consensus oligos were also purchased from Promega. Cytotoxicity assay TL1A- and Fas-induced cell death was determined using tetrazolium dye colorimetric test (MTS test). The MTS absorbance was then read using a plate reader at 490 nm. FIGURE 1. TRADD-deficient T cells do not proliferate in response to TL1A treatment. CFSE-labeled wild-type and knockout T cells were Results treated with TL1A (50 mg/ml; top panels) or IL-2 (100 U/ml; bottom TL1A can induce several events in T cells, including the activation panels) for 72 h, then stained with anti-CD4 or anti-CD8 Abs and analyzed of NF-kB and MAPK (7, 22). In addition, TL1A also enhances by flow cytometry. Histograms are gated on CD4+ (A) and CD8+ cells (B). 5214 THE ROLE OF TRADD IN DR3 SIGNALING

FIGURE 2. TRADD is required for MAPK and NF- kB activation. Western blot analysis of lysates of wild- type and TRADD knockout CD4+ (A), CD8+ (B) T cells, and pan T cells (C) treated with TL1A (50 mg/ ml) (A, B) for the indicated times or PMA (100 nM) (C). D, Nuclear extracts of wild-type and knockout T cells treated with TNF-a (30 ng/ml) and TL1A (50 mg/ml) for indicated times were analyzed by EMSA.

IkBa in CD3-activated T cells after TL1A treatment. As shown on with the previous results, TRADD, RIP, and TRAF2 were re- Downloaded from Fig. 2A and 2B, wild-type CD4+ and CD8+ T cells demonstrated cruited to DR3 after 5 min of TL1A treatment in wild-type T cells a potent activation of these two pathways. In contrast, TL1A in- (Fig. 3). Similar to TNFR1-associated RIP, DR3-associated RIP duced only a very weak phosphorylation of JNK and minimal was presumed to be ubiquitinated based on the pattern seen in phosphorylation of IkBa in TRADD-deficient T cells. Similar Western blotting with an anti-RIP Ab. In contrast, in TRADD- results were obtained if T cells were preactivated with CD3 in the deficient T cells, we observed neither RIP1 nor TRAF2 recruit- presence of CD28 or if they were not preactivated at all (data not ment to DR3, indicating that TRADD is required for the recruit- shown). This was true despite similar expression levels of DR3 in ment of these two critical signaling molecules to the DR3 sig- http://www.jimmunol.org/ wild-type and knockout cells (data not shown). The defect in naling complex in T cells. signaling was specific for TL1A because the PMA-dependent It has been shown previously that overexpression of DR3 in- activation of JNK was normal in both wild-type and TRADD duces apoptosis in cell lines (2–5), and the human leukemia cell knockout cells (Fig. 2C). Phosphorylation of p38 and ERK was line TF-1, which has high endogenous levels of DR3, undergoes not observed in response to TL1A stimulation, whereas both apoptosis when treated with TL1A in the presence of cyclohexi- kinases were strongly activated when T cells were treated with mide (7, 22). However, consistent with a previous study (7), we PMA (Supplemental Fig. 1). confirmed that primary T cells from lymph nodes were resistant to We also assessed NF-kB DNA-binding activity in wild-type cell death under these conditions (data not shown). We also tested by guest on September 26, 2021 T cells versus TRADD-deficient T cells using EMSA. TNF-a whether thymocytes can be sensitized to cell death. T cells from treatment was used as a positive control (Fig. 2D, lane 1). Strong wild-type and TRADD knockout mice were treated with cyclo- NF-kB DNA-binding activity was observed in wild-type T cells heximide and TL1A or anti-Fas Abs for 16 h. Apoptosis induced 30 min after TL1A treatment and was decreased by 4 h (Fig. 2D). by Fas cross-linking was the same in wild -type and TRADD- However, we observed little NF-kB binding to DNA in TRADD- deficient T cells in the presence or absence of both stimuli, and we observed little, if any, increase at 6 (Supplemental Fig. 2) or 8 h (not shown). Thus, our data suggest that TRADD is necessary for potent DR3-mediated signaling in response to TL1A. Based on the data obtained earlier from the overexpression experiments (2, 4), it is believed that, similar to TNFR1, DR3 interacts with TRADD, and then TRADD recruits RIP and TRAF proteins to the signaling complex. To observe the formation of the physiological DR3 signaling complex, we performed immuno- precipitation experiments with DR3-specific Abs. In agreement

FIGURE 4. TL1A does not induce apoptosis in primary T cells. MTS assay of the viability of wild-type and TRADD knockout T cells treated for FIGURE 3. TRADD is required for formation of the functional DR3 24 h with cycloheximide (C) alone (10 mg/ml), cycloheximide and TL1A signaling complex. Cell extracts from wild-type and TRADD knockout (50 mg/ml), or cycloheximide and anti-FAS (10 ng/ml) (A) and SMAC T cells treated with TL1A (50 mg/ml) for 5 min were immunoprecipitated mimetic (SM) alone (10 nM), SMAC mimetic and TL1A (50 mg/ml), or with anti-DR3 (ip:DR3) and analyzed by Western blotting. input, 2% of SMAC mimetic and anti-FAS (10 ng/ml) (B). Error bars shown represent extract before immunoprecipitation; Ub-, ubiquitinated. SEM. The Journal of Immunology 5215 deficient thymocytes (Fig. 4A, Supplemental Fig. 3). No cell death death in physiological contexts, in previous studies, TL1A has only was observed after TL1A treatment in the presence or absence been shown to induce apoptosis in overexpression systems and in of cycloheximide. Additionally, cross-linking of the flag-tagged immortalized cell lines that endogenously express DR3, whereas TL1A with the flag-specific M2 Abs did not result in apoptosis primary T cells, the likely physiological TL1A targets, did not of the T cells (data not shown). Furthermore, when the SMAC undergo cell death when treated with TL1A (7). Our findings are mimetic SM-164 was used instead of cycloheximide, it again consistent with this study, as we were unable to induce cell death sensitized thymocytes to Fas- but did not result in TL1A-induced in primary T cells in response to TL1A. Interestingly, the presence apoptosis (Fig. 4B). of cycloheximide, which usually sensitizes most TNFR1-express- ing cells to TNF-a–induced cell death, did not sensitize T cells to cell death. Particularly, although cellular inhibitor of apoptosis 2 Discussion (cIAP2) was found to be induced by TL1A in human TF-1 cells Due to the lack of knockout mice, the involvement of adapter (22), we did not observe any induction of cIAP2 in primary T cells protein TRADD in TNFR1 signaling had been a controversial issue following the engagement of TL1A (data not shown). Therefore, for a long time. Recently, our laboratory and others have generated the level of cIAP2 is not the main cause of the resistance of these TRADD knockout mice and have demonstrated that TRADD is cells to TL1A-induced apoptosis. Likewise, SMAC mimetic, al- indispensable for MAPK and NF-kB activation as well as apo- though sensitizing the primary T-cells to FasL, did not sensitize ptotic and necrotic cell death in TNFR1 signaling (18–20). In- the cells to TL1A. Although we did not examine this possibility, terestingly, TRADD turned out to be not solely a TNFR1 adaptor these data may suggest that DR3 is not capable of inducing the molecule, but also an adaptor in several other signaling pathways. formation of a secondary complex II-type complex (14) in which Downloaded from In the absence of TRADD, TRIF-dependent signaling events FADD is recruited and then activates caspase-8. Thus, in contrast downstream of TLR3 and TLR4 are attenuated, suggesting that to TNFR1 signaling that can activate both survival and death TRADD functions outside of DR signaling (18–20). TRADD has pathways depending on the cellular context, the TL1A–DR3 also been proposed to serve as a negative regulator of IFN-g pathway may be solely a proinflammatory and prosurvival path- signaling through the formation of a complex with STAT1a (24). way, rather than also acting as a proapoptotic pathway.

The antiviral pathways mediated through RIG-like helicases is DR3 has been implicated in many inflammatory and autoim- http://www.jimmunol.org/ also dependent on TRADD, and TRADD is a necessary adaptor to mune diseases including graft-versus-host disease (7), allergic lung mediate the downstream Cardif-dependent immune responses, inflammation (28), inflammatory bowel disease (8, 9), rheumatoid such as the activation of the NF-kB and IRF3 transcription factors arthritis, and experimental autoimmune encephalomyelitis (23, and the production of IFN-b (25). A role for TRADD in other DR 29). In all of the cases, TL1A plays an activating role, augmenting signaling pathways has also been suggested. The p75NTR receptor T cell responses and worsening the course of diseases, consistent was shown to interact with TRADD in breast cancer cells after with the fact that stimulation of DR3 does not lead to apoptosis in stimulation with nerve growth factor (26). Most other studies in primary T cells. Because TNF-a also plays an important role in relationship to other DR have relied on overexpression studies. inflammation in many of these diseases, and TRADD is involved For example, both DR4 and DR5 can interact with TRADD when in both DR3 and TNFR1 signaling pathways, approaches targeting by guest on September 26, 2021 overexpressed in cell lines (27). Likewise, the implication of the TRADD might be taken into consideration when designing new involvement of TRADD in the DR3 signaling pathway has also therapeutic strategies for treatment of inflammatory T cell-medi- largely been based on overexpression data. ated diseases. We took advantage of our recent generation of TRADD knockout mice and demonstrated that under more physiological conditions, Disclosures TRADD plays an important role in DR3 signaling. 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