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

JJ Lyons, Y Liu, CA Ma, X Yu, MP O'Connell… - Journal of Experimental …, 2017 - rupress.org
JJ Lyons, Y Liu, CA Ma, X Yu, MP O'Connell, MG Lawrence, Y Zhang, K Karpe, M Zhao…
Journal of Experimental Medicine, 2017rupress.org
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 …
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.
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