title: XEDAR activates the non-canonical NF-κB pathway.
abstract: Members of the tumor necrosis factor receptor (TNFR) superfamily are involved in a number of physiological and pathological responses by activating a wide variety of intracellular signaling pathways. The X-linked ectodermal dysplasia receptor (XEDAR; also known as EDA2R or TNFRSF27) is a member of the TNFR superfamily that is highly expressed in ectodermal derivatives during embryonic development and binds to ectodysplasin-A2 (EDA-A2), a member of the TNF family that is encoded by the anhidrotic ectodermal dysplasia (EDA) gene. Although XEDAR was first described in the year 2000, its function and molecular mechanism of action is still largely unclear. XEDAR has been reported to activate canonical nuclear factor κB (NF-κB) signaling and mitogen-activated protein (MAP) kinases. Here we report that XEDAR is also able to trigger the non-canonical NF-κB pathway, characterized by the processing of p100 (NF-κB2) into p52, followed by nuclear translocation of p52 and RelB. We provide evidence that XEDAR-induced p100 processing relies on the binding of XEDAR to TRAF3 and TRAF6, and requires the kinase activity of NIK and IKKα. We also show that XEDAR stimulation results in NIK accumulation and that p100 processing is negatively regulated by TRAF3, cIAP1 and A20.
authors.affiliation: Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. Electronic address: Kelly.Verhelst@irc.VIB-UGent.be.
authors.forename: Kelly
authors.initials: K
authors.lastname: Verhelst
authors.affiliation: Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. Electronic address: s.gardam@garvan.org.au.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gardam
authors.affiliation: Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. Electronic address: Alice.Borghi@irc.VIB-UGent.be.
authors.forename: Alice
authors.initials: A
authors.lastname: Borghi
authors.affiliation: Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. Electronic address: Marja.Kreike@irc.VIB-UGent.be.
authors.forename: Marja
authors.initials: M
authors.lastname: Kreike
authors.affiliation: Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. Electronic address: Isabelle.Carpentier@irc.VIB-UGent.be.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Carpentier
authors.affiliation: Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. Electronic address: Rudi.Beyaert@irc.VIB-UGent.be.
authors.forename: Rudi
authors.initials: R
authors.lastname: Beyaert
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D053331:Ectodysplasins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D052003:NF-kappa B p52 Subunit / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D053340:Xedar Receptor / Q000235:genetics* / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D004268:DNA-Binding Proteins; D053331:Ectodysplasins; D051550:I-kappa B Kinase; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; D052003:NF-kappa B p52 Subunit; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D048008:TNF Receptor-Associated Factor 3; D048029:TNF Receptor-Associated Factor 6; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D053340:Xedar Receptor; D000097782:NF-kappaB-Inducing Kinase; C506018:EDA protein, human; C506011:EDA2R protein, human; C090656:TRAF3 protein, human; C496559:CHUK protein, human; C076529:TNFAIP3 protein, human
keywords: EDA2R; Ectodermal dysplasia; Non-canonical; Nuclear factor-κB; XEDAR