title: Impaired dendritic-cell function in ectodermal dysplasia with immune deficiency is linked to defective NEMO ubiquitination.
abstract: Ectodermal dysplasia with immune deficiency (EDI) is caused by alterations in NEMO (nuclear factor [NF]-kappaB essential modulator). Most genetic mutations are located in exon 10 and affect the C-terminal zinc finger domain. However, the biochemical mechanism by which they cause immune dysfunction remains undetermined. In this report, we investigated the effect of a cysteine-to-arginine mutation (C417R) found in the NEMO zinc finger domain on dendritic cell (DC) function. Following CD40 stimulation of DCs prepared from 2 unrelated patients with the NEMO C417R mutation, we found NEMO ubiquitination was absent, and this was associated with preserved RelA but absent c-Rel activity. As a consequence, CD40 stimulated EDI DCs failed to synthesize the c-Rel-dependent cytokine interleukin-12, had impaired up-regulation of costimulatory molecules, and failed to support allogeneic lymphocyte proliferation in vitro. In contrast, EDI DCs stimulated with the TLR4 ligand lipopolysaccharide (LPS) showed normal downstream NF-kappaB activity, DC maturation, and NEMO ubiquitination. These findings show for the first time how mutations in the zinc finger domain of NEMO can lead to pathway specific defects in NEMO ubiquitination and thus immune deficiency.
authors.affiliation: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Stephane T
authors.initials: ST
authors.lastname: Temmerman
authors.forename: Chi A
authors.initials: CA
authors.lastname: Ma
authors.forename: Louis
authors.initials: L
authors.lastname: Borges
authors.forename: Marek
authors.initials: M
authors.lastname: Kubin
authors.forename: Shuying
authors.initials: S
authors.lastname: Liu
authors.forename: Jonathan M J
authors.initials: JM
authors.lastname: Derry
authors.forename: Ashish
authors.initials: A
authors.lastname: Jain
mesh_terms: D001120:Arginine / Q000737:chemistry; D017252:CD3 Complex / Q000096:biosynthesis; D019013:CD40 Antigens / Q000096:biosynthesis; D049109:Cell Proliferation; D003545:Cysteine / Q000737:chemistry; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism; D004476:Ectodermal Dysplasia / Q000276:immunology / Q000473:pathology*; D005091:Exons; D006801:Humans; D051550:I-kappa B Kinase / Q000737:chemistry* / Q000235:genetics*; D007153:Immunologic Deficiency Syndromes / Q000097:blood / Q000276:immunology*; D009154:Mutation; D017434:Protein Structure, Tertiary; D025801:Ubiquitin / Q000737:chemistry*; D016335:Zinc Fingers
chemical_list: D017252:CD3 Complex; D019013:CD40 Antigens; C491731:IKBKG protein, human; D025801:Ubiquitin; D001120:Arginine; D051550:I-kappa B Kinase; D003545:Cysteine