Human Molecular Genetics

Human Molecular Genetics Advance Access originally published online on October 26, 2005
Human Molecular Genetics 2005 14(23):3751-3757; doi:10.1093/hmg/ddi405

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TAB2, TRAF6 and TAK1 are involved in NF-B activation induced by the TNF-receptor, Edar and its adaptator Edaradd

Aurore Morlon^*, Arnold Munnich and Asma Smahi

Unité de Recherche sur les Handicaps Génétiques de l'Enfant INSERM U-393, Hôpital Necker-Enfants Malades, 149 rue de sèvres 75015 Paris, France

^* To whom correspondence should be addressed at: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries BP10142, 67404 Illkirch Cedex, France. Tel: +33 388653200; Fax: +33 388653201; Email: auroremorlon{at}hotmail.com

Received August 29, 2005; Accepted October 20, 2005

	ABSTRACT

TOP ABSTRACT INTRODUCTION RESULTS DISCUSSION MATERIALS AND METHODS REFERENCES

 
Activation of the NF-B pathway by the TNF-receptor Edar (Ectodysplasin receptor) and its downstream adaptator Edaradd (Edar-associated death domain) is essential for the development of hair follicles, teeth, exocrine glands and other ectodermal derivatives. Dysfunction of Edar signalling causes hypohidrotic/anhidrotic ectodermal dysplasia (ED), a disorder characterized by sparse hair, lack of sweat glands and malformation of teeth. The Edar signalling pathway stimulates NF-B transcription factors via an activation of the IB kinase (IKK) complex. To gain further insight into the mechanism of IKK activation by Edar and Edaradd, we performed a yeast two-hybrid screen and isolated TAB2 (TAK1-binding protein 2) as a binding partner of Edaradd. TAB2 is an adaptator protein that brigdes TRAF6 (TNF-receptor-associated factor 6) to TAK1 (TGFß-activated kinase 1), allowing TAK1 activation and subsequent IKK activation. Here, we show that endogenous and overexpressed TAB2, TRAF6 and TAK1 co-immunoprecipitated with Edaradd in 293 cells. Moreover, we show that dominant negative forms of TAB2, TRAF6 and TAK1 blocked the NF-B activation induced by Edaradd. These results support the involvement of the TAB2/TRAF6/TAK1 signalling complex in the Edar signal transduction pathway and have important implications for our understanding of NF-B activation and EDs in human.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION RESULTS DISCUSSION MATERIALS AND METHODS REFERENCES

 
The NF-B transcription factors play a crucial role in inflammatory and immune response, apoptosis, cellular proliferation and morphogenesis (1–4). In the past few years, several genetic diseases, including ectodermal dysplasias (EDs), have been ascribed to an alteration of the NF-B transduction pathway (5). In most cell types, NF-B is sequestered in the cytoplasm by IB proteins. Stimulation of cells by pro-inflammatory cytokines and other agents activates the IB kinase (IKK) complex, which is composed of two kinase subunits (IKK1/ and IKK2/ß) and a structural component (NEMO/IKK). Activation of IKK leads to phosphorylation of IBs, thus triggering their polyubiquitination, proteasomal degradation and ultimately the release of NF-B.

The Ectodysplasin receptor (Edar) is an NF-B-activating, death domain-containing, member of the TNF-receptor superfamily that signals through a unique cytoplasmic death domain-containing adaptator, Edaradd (6–9). Activation of Edar by its ligand, Ectodysplasin (EDA-A1), is essential for the proper development of ectodermal derivatives such as hair follicles, teeth and sweat glands (10,11). Consistently, mutations in the EDA, EDAR and EDARADD genes have been shown to cause hypohidrotic/anhidrotic ED which is characterized by sparse hair, abnormal or missing teeth and lack of sweat glands (8,9,12–16). Mutations in NEMO, the disease causing gene in incontinentia pigmenti, and in the IB gene have also been shown to cause ED (7,17–22). In these cases, ED is associated with other clinical manifestations such as immunodeficiency, osteopetrosis and lymphoedema.

Döffinger et al. (7) have previously shown that the Edar-mediated NF-B activation is IKK-dependent. To elucidate how Edar and Edaradd activate the IKK complex, we performed a yeast two-hybrid screen andisolated TAB2 (TAK1-binding protein 2) as a binding partner of Edaradd. In the interleukin-1 signalling pathway, TAB2 is an adaptator protein that binds TRAF6 (TNF-receptor-associated factor 6) to TAK1 (TGFß-activated kinase 1), allowing TAK1 activation and subsequent IKK activation. Here, we show that endogenous and overexpressed TAB2, TRAF6 and TAK1 co-immunoprecipitated with Edaradd in 293 cells. We also show that dominant negative forms of TAB2, TRAF6 and TAK1 blocked the NF-B activation induced by Edaradd. These results demonstrate the involvement of the TAB2/TRAF6/TAK1 complex in the Edar signal transduction pathway and provide a hypothetical mechanism of IKK activation by Edar and Edaradd.

	RESULTS

TOP ABSTRACT INTRODUCTION RESULTS DISCUSSION MATERIALS AND METHODS REFERENCES

 
Identification of TAB2 as a new binding partner of Edaradd by yeast two-hybrid screen
In order to ultimately elucidate how Edar and Edaradd activate the IKK complex, we performed a yeast two-hybrid screen to identify Edaradd-interacting proteins. We screened a human keratinocyte cDNA library using the full-length human EDARADD cDNA as a bait and obtained 100 positive clones. ß-galactosidase reporter assays (Fig. 1A) and growth in selective media (data not shown) showed that clone 9 interacted efficiently and specifically with Edaradd. Data bank searches revealed that this clone corresponded to part of the sequence encoding TAB2 (TAK1-binding protein 2) (Fig. 1B). TAB2 is a 694 amino acid protein composed of an N-terminal CUE domain (amino acids 8–50), a C-terminal Znf-RanGDP domain (amino acids 663–693) and two coiled-coil domains (amino acids 537–578 and amino acids 592–619). Clone 9 encoded an N-terminal truncated TAB2 protein (amino acids 180–693), suggesting that the region amino acids 1–180 is not required for interaction with Edaradd.

View larger version (31K): [in this window] [in a new window]   Figure 1. Isolation of TAB2 as an interactor of Edaradd by two-hybrid screen. (A)ß-galactosidase levels in yeasts containing the Gal1 upstream activation sequence (UAS)-Lac Z reporter (Y187 strain), transformed with the indicated constructs. LaminC, Gal4-DBD and Gal4-AD were negative controls. Results from the ß-galactosidase assay are reported in Miller units as a mean of at least three independent experiments, each done in triplicate. (B) TAB2 sequence with indication of ‘clone 9’ (underlined in grey).

 
TAB2 interacts with Edaradd in mammalian cells
In order to confirm the interaction of TAB2 with Edaradd in mammalian cells, we transfected 293 cells with Flag-TAB2 and HA-Edaradd expression vectors. Cell extracts were immunoprecipitated using both anti-HA and anti-TAB2 antibodies. Western blot analyses showed that TAB2 only immunoprecipitated when expressed concomitantly with Edaradd (Fig. 2A, lanes 10–12). Conversely, HA-Edaradd was detected in anti-TAB2 immunoprecipitates from TAB2 co-transfectants, but not in cells transfected with HA-Edaradd or TAB2 constructions alone (Fig. 2A, lanes 13–15). These data suggest that TAB2 interacts with Edaradd when overexpressed in 293 cells.

View larger version (23K): [in this window] [in a new window]   Figure 2. Interaction of TAB2 with Edaradd in mammalian cells. HEK 293T cells were transfected with the Flag-TAB2 and the HA-Edaradd expression vectors as indicated. Cells were harvested 48 h after transfection, and lysates were subjected to IP with both anti-HA and anti-TAB2 antibodies. Whole extracts (top panel) and immunocomplexes were analysed by western blotting using both anti-HA and anti-TAB2 antibodies (middle and bottom panels).

 
TRAF6 and TAK1 co-immunoprecipitate with Edaradd
In IL-1 signalling pathway, TAB2 functions as an adaptor that bridges the TNF-receptor-associated factor TRAF6 to the TGF-ß–activated kinase TAK1 (23). The recruitment of TAK1 to the TRAF6 complex results in TAK1 activation and subsequent IKK activation (24).The involvement of TRAF6 in Edar signalling is supported by the observation of hypohidrotic ED in TRAF6-deficient mice (25). Considering that Edaradd contains a TRAF-binding site, we have tested the interaction of Edaradd with TRAF6 in 293 cells transfected with both HA-Edaradd and Flag-TRAF6 constructs (Fig. 3A). Cell lysates were subjected to immunoprecipitation (IP) with anti-HA antibodies. Western blot analyses of whole-cell extracts and immunocomplexes with anti-TRAF6 antibodies revealed that Flag-TRAF6, but also endogenous TRAF6, co-immunoprecipitated with HA-Edaradd.

View larger version (21K): [in this window] [in a new window]   Figure 3. TRAF6 and TAK1 co-immunoprecipitate with Edaradd. (A) HEK 293T cells were transfected with the Flag-TRAF6 and the HA-Edaradd expression vectors as indicated. Cells were harvested 48 h after transfection, and lysates were subjected to IP with the anti-HA antibody. Whole extracts (top panel) and immunocomplexes were analysed by western blotting using both anti-HA and anti-TRAF6 antibodies (bottom panel). (B) 293T cells were co-transfected with the expression plasmids encoding Flag-TAK1 and HA-Edaradd as described. Cell lysates were immunoprecipitated with the anti-HA antibody. Whole extracts (top panel) and immunocomplexes were analysed by western blotting using anti-HA and anti-TAK1 antibodies (bottom panel).

 
TAK1 also immunoprecipitated with Edaradd when both proteins were overexpressed in 293 cells. Indeed, Flag-TAK1 was detected in anti-HA immunoprecipitates from Flag-TAK1/HA-Edaradd co-transfectants, but not in cells transfected with either HA-Edaradd or Flag-TAK1 alone (Fig. 3B).

Endogenous TAB2/TRAF6/TAK1 complex immunoprecipitates with Edaradd
We then tested the interaction among endogenous TAB2, TRAF6 and TAK1 with Edaradd in 293 cells. Lysates of cells co-transfected with Edar and HA-Edaradd expression vectors were subjected to IP with anti-HA antibodies. Western blot analyses of lysates and immunoprecipitates using anti-TAB2, anti-TRAF6 and anti-TAK1 antibodies revealed that endogenous TAB2, TRAF6 and TAK1 co-immunoprecipitated with Edaradd (Fig. 4). Interestingly, endogenous TAB2, TRAF6 and TAK1 were not able to immunoprecipitate with Edaradd in 293 cells transfected with the HA-Edaradd expression vector only (data not shown).

View larger version (60K): [in this window] [in a new window]   Figure 4. The endogenous TAB2/TRAF6/TAK1 complex immunoprecipitates with Edaradd. Lysates of HEK 293T cells co-transfected with the pCMV-Edar and pCMV-HA-Edaradd vectors were subjected to IP with anti-HA antibodies. Whole extracts and immunocomplexes were analysed by western blotting using anti-TAB2, anti-TRAF6 and anti-TAK1 antibodies.

 
Role of TAB2, TRAF6 and TAK1 in Edar signalling
In order to test the physiological relevance of the interactions among TAB2, TRAF6, TAK1 and Edaradd on Edar signalling, we performed trans-activation assays in 293 cells. Cells were transfected with a luciferase reporter gene under the control of NF-B binding sites, an Edaradd expression vector and increasing amounts of dominant negative forms of TAB2, TAK1 and TRAF6 (Fig. 5). It has been previously shown that a truncated form of TAB2 (TAB2C) inhibits IL-1-induced NF-B activation (23). Our results show that TAB2C inhibited Edaradd-induced NF-B activation in a dose-dependent manner, demonstrating that TAB2 is involved in Edaradd signalling (Fig. 5).

View larger version (13K): [in this window] [in a new window]   Figure 5. Effects of the dominant negative forms of TAB2, TAK1 and TRAF6 on Edaradd-induced NF-B activation. HEK293T cells were transiently transfected with pIg-Luc, pRenilla and the Edaradd expression plasmid along with increasing amounts of TAB2C, TAK1 (K63W) and TRAF6 expression vector as indicated. Cells were harvested 48 h later and assayed for luciferase expression. Luciferase activity was normalized relative to renilla activity. Data were expressed in percentage of induction. Activation of the Ig-Luc reporter plasmid by Edaradd is considered as 100% of induction. Each experiment was performed three times in triplicate.

 
Similarly, co-transfection of increasing amounts of the kinase-inactive form of TAK1 (K63W) also resulted in a dose-dependent inhibition of Edaradd-induced NF-B activation (Fig. 4). These data suggest that the kinase activity of TAK1 is required for Edar signalling.

Moreover, Edaradd-mediated NF-B activation was blocked by co-expression of a truncated version of TRAF6 (TRAF6), which acted as a dominant negative inhibitor of NF-B activation in the IL-1 pathway (26). These results support the involvement of TRAF6 in Edar signalling, thus explaining the phenotypical similarities between TRAF6-deficient mice and Crinkled, Tabby and Downless, the mutant mouse models inactivated for the Edaradd, Ectodysplasin and Edar genes, respectively.

	DISCUSSION

TOP ABSTRACT INTRODUCTION RESULTS DISCUSSION MATERIALS AND METHODS REFERENCES

 
Activation of NF-B by the TNF-receptor Edar is essential for the development of hair follicles, teeth, exocrine glands and other ectodermal derivatives (11). Dysfunction of the Edar signalling pathway causes hypohidrotic/anhidrotic ED, a disorder characterized by sparse hair, lack of sweat glands and malformation of teeth (5,27). Edar is a death domain-containing receptor that signals through a unique death domain-containing adaptator Edaradd (8,9). It has been previously shown that Edar-induced NF-B activation is IKK-dependent (7). However, how Edar and Edaradd mediate IKK activation was hitherto unknown.

In order to elucidate how Edar and Edaradd activate the IKK complex, we performed a yeast two-hybrid screen and isolated TAB2 as a new binding partner of Edaradd. TAB2 is an adaptator protein that was known to be involved in other NF-B-activating signalling pathways, namely, IL-1/TLR or RANK. In IL-1 signalling, the role of TAB2 is to brigde the protein kinase TAK1 to the TRAF6 adaptator, allowing TAK1 activation and subsequent IKK activation.

Here, we provide several lines of evidence supporting the involvement of the TAB2/TRAF6/TAK1 complex in the Edar signal transduction pathway. First, TAB2, TRAF6 and TAK1 interact with Edaradd when overexpressed in 293 cells. Secondly, endogenous TAB2, TRAF6 and TAK1 immunoprecipitated with Edaradd in 293 cells overexpressing Edaradd and Edar. Thirdly, dominant negative forms of TAB2, TRAF6 and TAK1 blocked the Edaradd-induced NF-B activation in 293 cells. Taken together, these results suggest that the TRAF6/TAB2/TAK1 signalling complex mediates IKK activation by Edar and Edaradd (Fig. 6).

View larger version (21K): [in this window] [in a new window]   Figure 6. Proposed model for the Edar signalling pathway. The binding of the ligand Ectodysplasin (EDA-A1) to the TNF-receptor Edar results in the formation of a complex containing Edaradd, TRAF6, TAB2 and TAK1. TAK1 activates the IKK complex either directly or via activation of NIK, which in turn phosphorylates IKK. Activation of the IKK complex leads to ubiquitination and proteasomal degradation of the inhibitory proteins IB and to the release of the NF-B transcription factor. NF-B translocates into the nucleus where it activates the transcription of target genes. Termination mediated by the Edar pathway is CYLD, possibly by deubiquitinating the TRAF6 protein.

 
How these molecules are activated and switched off remains yet unanswered. After stimulation by IL-1, the IL-1 receptor recruits accessory proteins and the serine–threonine kinase IRAK. Activation of IRAK is essential for the subsequent activation of the TRAF6/TAK1/TAB2 complex. The fact that IRAK, like Edar and Edaradd, possesses a death domain suggests that IRAK is also possibly involved in Edar signalling. Moreover, it has been shown that during IL-1 signalling, TRAF6 polyubiquitination promotes activation of the TAB1/TAK1/TAB2 complex through various ubiquitination and phosphorylation events. Recent studies have shown that mutations in CYLD, a deubiquitinating enzyme involved in Edar signalling, account for familial cylindromatosis (a predisposition for developing tumours of hair follicle and eccrine glands, the structures that are missing in ED) and promote deubiquitination of TRAF6 (28–31). Considering the involvement of TRAF6 in the Edar pathway, it is conceivable that CYLD acts as a silencer of Edar signalling by regulating TRAF6 ubiquitination.

Our results also suggest that the kinase activity of TAK1 is required for Edar signalling because of its ability to directly phosphorylate the IKK complex (24). Another possible mechanism of IKK activation by TAK1 may be in the indirect activation of IKK via the NF-B-inducing kinase NIK. Indeed, TAK1 is also able to phosphorylate NIK, which can in turn phosphorylate the IKK complex (32,33). The observation that dominant negative forms of NIK block Edar-induced NF-B activation supports this second hypothesis (6).

According to our results, the TRAF6/TAB2/TAK1 signalling complex, which was initially shown to be involved in IL-1 signalling, appears to be also involved in the signalling of the TNF-receptor Edar. These results emphasize the widespread role of the TRAF6/TAB2/TAK1 complex in signalling NF-B activation, as this complex is not only involved in IL-1/TLR signalling, but also in the signalling of several members of TNF-receptor superfamily, including Edar or RANK. These results support the novel idea that the TRAF6/TAB2/TAK1 complex could be the converging point of the majority of NF-B signalling pathways.Thus, our results have important implications for our understanding of NF-B activation by diverse stimuli. These findings are also relevant for our understanding of the pathophysiology of ED. Indeed, the involvement of TAB2, TRAF6 and TAK1 in Edar signalling suggests that they are good candidate genes for ED. The implication of TAB2, TRAF6 and TAK1 in other signalling pathways, such as IL-1 or RANK, suggests that mutations in these genes could be responsible for ED associated with immunodeficiency and/or osteopetrosis, as is the case for some NEMO mutations (7).

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION RESULTS DISCUSSION MATERIALS AND METHODS REFERENCES

 
Yeast two-hybrid screening
Yeast two-hybrid screening was performed using the MATCHMAKER Two-hybrid system 3, according to the manufacturer's protocol (BD Biosciences Clontech, Palo Alto, CA, USA). pGBKT7-Edaradd was subcloned from pCDNA-HA-Edaradd vector using PCR methods. A human keratinocyte cDNA library (BD Biosciences Clontech) was co-transformed with the pGBKT7-Edaradd bait plasmid in AH 109 yeasts. Co-transformants were selected in SD plates lacking histidine, leucine and tryptophane and containing X--Gal (BD biosciences Clontech).

Co-immunoprecipitation and western blottingexperiments
HEK293T cells were plated at a density of 10x10⁵ in 10 cm diameter dishes and transfected with 5 µg of each plasmid by the calcium phosphate precipitation technique. Total amount of DNA was kept constant by adding pCDNA plasmid as necessary. Cells were collected in 1 ml EBC (50 mM Tris–HCl pH 8, 170 mM NaCl, 0.5% NP-40, 50 mM NaF) containing 1 mM of PMSF and 10 µg/ml of aprotinin and leupeptin. After preclearing for 1 h with 50 µl of a slurry of protein A– or protein G–Sepharose, the supernatants were incubated overnight at 4°C with anti-HA (Santa Cruz) or anti-TAB2 (Affinity Bioreagents) antibodies and then incubated for 1 h with 50 µl of a slurry of protein A– or protein G–Sepharose. Beads were washed three times in EBC and resuspended in 50 µl of SDS loading buffer for western blot analysis. Anti-TRAF6 and anti-TAK1 antibodies were purchased from Santa Cruz Biotechnologies.

For co-immunoprecipitation of endogenous TAB2, TRAF6 and TAK1, HEK293 cells grown in six-well plates were co-transfected with 1 µg of pCMV-Edar and 1 µg of pCMV-HA-Edaradd with Polyfect® transfection reagent, according to the manufacturer's instructions (Qiagen). Cells were harvested 24 h after transfection, and IP with anti-HA antibodies was performed as previously described.

Transient transfection and reporter assays
HEK293T cells grown in six-well plates were transfected by the calcium phosphate precipitation technique with 0.25 µg of IgK-Luc, 0.1 µg of pRenilla, 0.5 µg of pCDNA-HA-Edaradd and increasing amount of expression vectors encoding the dominant negative forms of TAB2, TAK1 and TRAF6. Total amount of DNA was adjusted to 5 µg by adding pCDNA vector as necessary. Luciferase activity was measured using the Dual-Luciferase Reporter Assay System (Promega) 48 h after transfection, according to the manufacturer's protocol.

	ACKNOWLEDGEMENTS

 
We are grateful to Dr Chen, Dr Courtois and Dr Matsumoto for providing us plasmids and reagents. We thank Dr I. Davidson and Dr P. Sassone-Corsi for helpful discussion. This work was supported by Association pour la Recherche contre le Cancer (ARC).

Conflict of Interest statement. The authors have no conflict of interest.

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