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ERBIN deficiency links STAT3 and TGF-beta pathway defects with atopy in humans

  1. Author:
    Lyons, J. J.
    Liu, Y.
    Ma, C. A.
    Yu, X.
    O'Connell, M. P.
    Lawrence, M. G.
    Zhang, Y.
    Karpe, K.
    Zhao, M.
    Siegel, A. M.
    Stone, K. D.
    Nelson, C.
    Jones, Nina
    DiMaggio, T.
    Darnell, D. N.
    Mendoza-Caamal, E.
    Orozco, L.
    Hughes, J. D.
    McElwee, J.
    Hohman, R. J.
    Frischmeyer-Guerrerio, P. A.
    Rothenberg, M. E.
    Freeman, A. F.
    Holland, S. M.
    Milner, J. D.

  2. Author Address

    NIAID, Genet & Pathogenesis Allergy Sect, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.NIAID, Res Technol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.NIAID, Food Allergy Res Unit, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.Univ Virginia, Dept Med, Div Asthma Allergy & Immunol, Charlottesville, VA 22903 USA.Leidos Biomed Res Inc, Clin Res Directorate CRMP, NCI Campus Frederick, Frederick, MD 21702 USA.Natl Inst Genom Med, Mexico City 14610, DF, Mexico.Merck & Co Inc, Merck Res Labs, Boston, MA 02115 USA.Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Allergy & Immunol, Cincinnati, OH 45229 USA.
    1. Year: 2017
    2. Date: 2017-03-01
  2. Journal: JOURNAL OF EXPERIMENTAL MEDICINE
  3. ROCKEFELLER UNIV PRESS,
    1. 214
    2. 3
    3. Pages: 669-680
  5. Type of Article: Article
  6. ISSN: 0022-1007
  1. 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-beta 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-beta signaling via ERBB2-interacting protein (ERBIN), a SMAD anchor for receptor activation and SMAD2/3 binding protein. Individuals with dominant-negative STAT3 mutations (STAT3(mut)) or a loss-of-function mutation in ERBB2IP (ERBB2IP(mut)) have evidence of deregulated TGF-beta 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-beta. In turn, cell-intrinsic deregulation of TGF-beta signaling is associated with increased functional IL-4R alpha expression on naive lymphocytes and can induce expression and activation of the IL-4/IL-4R alpha/GATA3 axis in vitro. These findings link increased TGF-beta pathway activation in ERBB2IP(mut) and STAT3(mut) patient lymphocytes with increased T helper type 2 cytokine expression and elevated IgE.

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External Sources

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  2. DOI: 10.1084/jem.20161435
  3. PMID: 28126831
  4. PMCID: PMC5339676
  5. View record in Web of Science®
  6. WOS: 000395828600008

Library Notes

  1. Fiscal Year: FY2016-2017
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