title: ERBIN deficiency links STAT3 and TGF-β pathway defects with atopy in humans.
abstract: Nonimmunological connective tissue phenotypes in humans are common among some congenital and acquired allergic diseases. Several of these congenital disorders have been associated with either increased TGF-β activity or impaired STAT3 activation, suggesting that these pathways might intersect and that their disruption may contribute to atopy. In this study, we show that STAT3 negatively regulates TGF-β signaling via ERBB2-interacting protein (ERBIN), a SMAD anchor for receptor activation and SMAD2/3 binding protein. Individuals with dominant-negativeSTAT3mutations (STAT3mut) or a loss-of-function mutation inERBB2IP(ERBB2IPmut) have evidence of deregulated TGF-β signaling with increased regulatory T cells and total FOXP3 expression. These naturally occurring mutations, recapitulated in vitro, impair STAT3-ERBIN-SMAD2/3 complex formation and fail to constrain nuclear pSMAD2/3 in response to TGF-β. In turn, cell-intrinsic deregulation of TGF-β signaling is associated with increased functional IL-4Rα expression on naive lymphocytes and can induce expression and activation of the IL-4/IL-4Rα/GATA3 axis in vitro. These findings link increased TGF-β pathway activation inERBB2IPmutandSTAT3mutpatient lymphocytes with increased T helper type 2 cytokine expression and elevated IgE.
authors.affiliation: Genetics and Pathogenesis of Allergy Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: J J
authors.identifier: 0000-0002-2346-8189
authors.initials: JJ
authors.lastname: Lyons
authors.affiliation: Genetics and Pathogenesis of Allergy Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Genetics and Pathogenesis of Allergy Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: C A
authors.initials: CA
authors.lastname: Ma
authors.affiliation: Genetics and Pathogenesis of Allergy Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: X
authors.identifier: 0000-0002-6981-5772
authors.initials: X
authors.lastname: Yu
authors.affiliation: Genetics and Pathogenesis of Allergy Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: M P
authors.initials: MP
authors.lastname: O'Connell
authors.affiliation: Division of Asthma, Allergy, and Immunology, Department of Medicine, University of Virginia, Charlottesville, VA 22903.
authors.forename: M G
authors.initials: MG
authors.lastname: Lawrence
authors.affiliation: Genetics and Pathogenesis of Allergy Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Y
authors.identifier: 0000-0001-9932-917X
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Genetics and Pathogenesis of Allergy Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: K
authors.initials: K
authors.lastname: Karpe
authors.affiliation: Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: M
authors.identifier: 0000-0002-5700-2950
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Genetics and Pathogenesis of Allergy Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: A M
authors.identifier: 0000-0003-4913-570X
authors.initials: AM
authors.lastname: Siegel
authors.affiliation: Genetics and Pathogenesis of Allergy Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: K D
authors.initials: KD
authors.lastname: Stone
authors.affiliation: Genetics and Pathogenesis of Allergy Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: C
authors.initials: C
authors.lastname: Nelson
authors.affiliation: Clinical Research Directorate/CRMP, Leidos Biomedical Research Inc., NCI Campus at Frederick, Frederick, MD 21702.
authors.forename: N
authors.identifier: 0000-0003-3382-5589
authors.initials: N
authors.lastname: Jones
authors.affiliation: Genetics and Pathogenesis of Allergy Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: T
authors.initials: T
authors.lastname: DiMaggio
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: D N
authors.initials: DN
authors.lastname: Darnell
authors.affiliation: National Institute of Genomic Medicine, 14610 Mexico City, Mexico.
authors.forename: E
authors.identifier: 0000-0002-6224-6829
authors.initials: E
authors.lastname: Mendoza-Caamal
authors.affiliation: National Institute of Genomic Medicine, 14610 Mexico City, Mexico.
authors.forename: L
authors.identifier: 0000-0002-5801-9180
authors.initials: L
authors.lastname: Orozco
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., Boston, MA 02115.
authors.forename: J D
authors.identifier: 0000-0002-8965-5382
authors.initials: JD
authors.lastname: Hughes
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., Boston, MA 02115.
authors.forename: J
authors.identifier: 0000-0002-4888-7152
authors.initials: J
authors.lastname: McElwee
authors.affiliation: Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: R J
authors.identifier: 0000-0003-0178-0494
authors.initials: RJ
authors.lastname: Hohman
authors.affiliation: Food Allergy Research Unit, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: P A
authors.initials: PA
authors.lastname: Frischmeyer-Guerrerio
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
authors.forename: M E
authors.initials: ME
authors.lastname: Rothenberg
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: A F
authors.identifier: 0000-0001-7005-8345
authors.initials: AF
authors.lastname: Freeman
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: S M
authors.initials: SM
authors.lastname: Holland
authors.affiliation: Genetics and Pathogenesis of Allergy Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 jdmilner@niaid.nih.gov.
authors.forename: J D
authors.identifier: 0000-0002-3913-3869
authors.initials: JD
authors.lastname: Milner
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000502:physiology*; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology*; D015847:Interleukin-4 / Q000502:physiology; D019948:Receptors, Interleukin-4 / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein / Q000032:analysis / Q000502:physiology; D051900:Smad3 Protein / Q000032:analysis / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C413364:ERBIN protein, human; D019948:Receptors, Interleukin-4; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D015847:Interleukin-4