title: Recruitment of A20 by the C-terminal domain of NEMO suppresses NF-κB activation and autoinflammatory disease.
abstract: Receptor-induced NF-κB activation is controlled by NEMO, the NF-κB essential modulator. Hypomorphic NEMO mutations result in X-linked ectodermal dysplasia with anhidrosis and immunodeficiency, also referred to as NEMO syndrome. Here we describe a distinct group of patients with NEMO C-terminal deletion (ΔCT-NEMO) mutations. Individuals harboring these mutations develop inflammatory skin and intestinal disease in addition to ectodermal dysplasia with anhidrosis and immunodeficiency. Both primary cells from these patients, as well as reconstituted cell lines with this deletion, exhibited increased IκB kinase (IKK) activity and production of proinflammatory cytokines. Unlike previously described loss-of-function mutations, ΔCT-NEMO mutants promoted increased NF-κB activation in response to TNF and Toll-like receptor stimulation. Investigation of the underlying mechanisms revealed impaired interactions with A20, a negative regulator of NF-κB activation, leading to prolonged accumulation of K63-ubiquitinated RIP within the TNFR1 signaling complex. Recruitment of A20 to the C-terminal domain of NEMO represents a novel mechanism limiting NF-κB activation by NEMO, and its absence results in autoinflammatory disease.
authors.affiliation: Immunodeficiency and Inflammation Unit, Autoimmunity Branch, National Institute of Arthritis, Musculoskeletal and Skin Disease, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Jevgenia
authors.initials: J
authors.lastname: Zilberman-Rudenko
authors.affiliation: University of Pennsylvania School of Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104;
authors.forename: Linda Monaco
authors.initials: LM
authors.lastname: Shawver
authors.affiliation: Immunodeficiency and Inflammation Unit, Autoimmunity Branch, National Institute of Arthritis, Musculoskeletal and Skin Disease, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Alex W
authors.initials: AW
authors.lastname: Wessel
authors.affiliation: Immunodeficiency and Inflammation Unit, Autoimmunity Branch, National Institute of Arthritis, Musculoskeletal and Skin Disease, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Yongquan
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis, Musculoskeletal and Skin Disease, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Martin
authors.initials: M
authors.lastname: Pelletier
authors.affiliation: Translational Immunology Section, Office of Science and Technology, National Institute of Arthritis, Musculoskeletal and Skin Disease, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Wanxia Li
authors.initials: WL
authors.lastname: Tsai
authors.affiliation: Immunodeficiency and Inflammation Unit, Autoimmunity Branch, National Institute of Arthritis, Musculoskeletal and Skin Disease, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Younglang
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Immunodeficiency and Inflammation Unit, Autoimmunity Branch, National Institute of Arthritis, Musculoskeletal and Skin Disease, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Spiridon
authors.initials: S
authors.lastname: Vonortas
authors.affiliation: Department of Pediatrics, University of California, San Francisco School of Medicine, San Francisco, CA 94143;
authors.forename: Laurence
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Ashwell
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
authors.affiliation: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis, Musculoskeletal and Skin Disease, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Richard M
authors.initials: RM
authors.lastname: Siegel
authors.affiliation: Immunodeficiency and Inflammation Unit, Autoimmunity Branch, National Institute of Arthritis, Musculoskeletal and Skin Disease, National Institutes of Health, Bethesda, MD 20892; eric.hanson@nih.gov.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hanson
mesh_terms: D016022:Case-Control Studies; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D000074749:Deubiquitinating Enzyme CYLD; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D051550:I-kappa B Kinase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D009000:Monocytes / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010375:Pedigree; D010641:Phenotype; D025821:Polyubiquitin / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; C491731:IKBKG protein, human; D047908:Intracellular Signaling Peptides and Proteins; D050505:Mutant Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D018124:Receptors, Tumor Necrosis Factor; D051193:Toll-Like Receptors; D025521:Tumor Suppressor Proteins; D025821:Polyubiquitin; D051550:I-kappa B Kinase; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
keywords: A20; HED-ID; NF-κB; TLR; autoinflammatory disease