title: Dendritic cells from humans with hypomorphic mutations in IKBKG/NEMO have impaired mitogen-activated protein kinase activity.
abstract: The covalent attachment of lysine 63-linked polyubiquitin to the zinc-finger domain of IKBKG/NEMO (also known as IKKγ) is necessary for full activation of NF-κB. Impairments of this biochemical mechanism explain the deleterious effects of hypomorphic NEMO mutations on NF-κB signaling function in humans suffering from X-linked ectodermal dysplasia and immunodeficiency. Nevertheless, the biological function of the NEMO zinc-finger domain in the regulation of mitogen-activated protein kinase (MAPK) activity is poorly understood. Here we show that dendritic cells from patients with EDI caused by a C-terminal E391X deletion of the zinc finger of NEMO exhibit impaired MAPK activation in response to lipopolysaccharide (LPS) stimulation. Interestingly, DCs from patients with a C417R missense mutation within the zinc finger domain of NEMO in which ubiquitination of NEMO is preserved are also defective in JNK and ERK activity following LPS stimulation. Our findings indicate that the structural integrity of the NEMO ZF domain is more important than its polyubiquitination for full activation of the MAPK. Furthermore, phosphorylation and polyubiquitination of upstream TAK1 were significantly reduced in the E391X zinc-finger deleted patients, indicating that the NEMO zinc finger may play an important role in assembling the proximal signaling complex for MAPK activation.
authors.affiliation: Laboratory of Host Defenses, NIAID, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Chi A
authors.initials: CA
authors.lastname: Ma
authors.forename: Hong-Ying
authors.initials: HY
authors.lastname: Wang
authors.forename: Stephane
authors.initials: S
authors.lastname: Temmerman
authors.forename: Yongge
authors.initials: Y
authors.lastname: Zhao
authors.forename: Liming
authors.initials: L
authors.lastname: Wu
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Hornung
authors.forename: Diane
authors.initials: D
authors.lastname: Wara
authors.forename: Ashish
authors.initials: A
authors.lastname: Jain
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000378:metabolism*; D004476:Ectodermal Dysplasia / Q000201:enzymology* / Q000235:genetics* / Q000276:immunology; D040181:Genetic Diseases, X-Linked; D006801:Humans; D051550:I-kappa B Kinase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D007153:Immunologic Deficiency Syndromes / Q000201:enzymology* / Q000235:genetics* / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D000081207:Primary Immunodeficiency Diseases; D017384:Sequence Deletion; D054875:Ubiquitination; D016335:Zinc Fingers / Q000235:genetics; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D016207:Cytokines; D051550:I-kappa B Kinase; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D000099151:MAP Kinase Kinase Kinase 7; C491731:IKBKG protein, human