title: Defective nuclear IKKα function in patients with ectodermal dysplasia with immune deficiency.
abstract: Ectodermal dysplasia with immune deficiency (EDI) is an immunological and developmental disorder caused by alterations in the gene encoding NF-κB essential modulator (NEMO; also known as IκB kinase γ subunit [IKKγ]). Missense mutations in the gene encoding NEMO are associated with reduced signal-induced nuclear translocation of NF-κB proteins, resulting in defective expression of NF-κB target genes. Here, we report 2 unrelated male patients with EDI, both of whom have normal NEMO coding sequences, but exhibit a marked reduction in expression of full-length NEMO protein. TLR4 stimulation of APCs from these patients induced normal cytoplasmic activation and nuclear translocation of NF-κB. However, cells deficient in full-length NEMO were defective in expression of NF-κB-regulated cytokines, such as IL-12, suggesting a downstream defect in chromatin accessibility for NF-κB transcription factors. TLR4-stimulated APCs from the patients were defective in IKKα-dependent H3 histone phosphorylation at the IL-12 promoter and recruitment of NF-κB heterodimers RelA and cRel to the promoter. Expression of a super-active form of IKKα restored IL-12 production in a NEMO knockdown human monocytic cell line following LPS treatment. Our findings suggest that NEMO regulates the nuclear function of IKKα and offer new insights into the mechanisms underlying diminished NF-κB signaling in patients with EDI.
authors.affiliation: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Stephane T
authors.initials: ST
authors.lastname: Temmerman
authors.forename: Chi A
authors.initials: CA
authors.lastname: Ma
authors.forename: Yongge
authors.initials: Y
authors.lastname: Zhao
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Keenan
authors.forename: Ivona
authors.initials: I
authors.lastname: Aksentijevich
authors.forename: Margaret
authors.initials: M
authors.lastname: Fessler
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Brown
authors.forename: Alan
authors.initials: A
authors.lastname: Knutsen
authors.forename: Ralph
authors.initials: R
authors.lastname: Shapiro
authors.forename: Ashish
authors.initials: A
authors.lastname: Jain
mesh_terms: D000293:Adolescent; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002675:Child, Preschool; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004476:Ectodermal Dysplasia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D015321:Gene Rearrangement; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D000081207:Primary Immunodeficiency Diseases; D011401:Promoter Regions, Genetic; D020569:Proto-Oncogene Proteins c-rel; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; C491731:IKBKG protein, human; D016328:NF-kappa B; D009687:Nuclear Proteins; D020569:Proto-Oncogene Proteins c-rel; C068059:REL protein, human; C498143:RELA protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D018664:Interleukin-12; D051550:I-kappa B Kinase