Format

Send to

Choose Destination
J Exp Med. 2017 Mar 6;214(3):669-680. doi: 10.1084/jem.20161435. Epub 2017 Jan 26.

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

Author information

1
Genetics and Pathogenesis of Allergy Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
2
Division of Asthma, Allergy, and Immunology, Department of Medicine, University of Virginia, Charlottesville, VA 22903.
3
Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
4
Clinical Research Directorate/CRMP, Leidos Biomedical Research Inc., NCI Campus at Frederick, Frederick, MD 21702.
5
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
6
National Institute of Genomic Medicine, 14610 Mexico City, Mexico.
7
Merck Research Laboratories, Merck & Co. Inc., Boston, MA 02115.
8
Food Allergy Research Unit, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
9
Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
10
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.

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-negative STAT3 mutations (STAT3mut ) or a loss-of-function mutation in ERBB2IP (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 in ERBB2IPmut and STAT3mut patient lymphocytes with increased T helper type 2 cytokine expression and elevated IgE.

PMID:
28126831
PMCID:
PMC5339676
DOI:
10.1084/jem.20161435
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center