| First Author | Lyons JJ | Year | 2017 |
| Journal | J Exp Med | Volume | 214 |
| Issue | 3 | Pages | 669-680 |
| PubMed ID | 28126831 | Mgi Jnum | J:240952 |
| Mgi Id | MGI:5896871 | Doi | 10.1084/jem.20161435 |
| Citation | Lyons JJ, et al. (2017) ERBIN deficiency links STAT3 and TGF-beta pathway defects with atopy in humans. J Exp Med 214(3):669-680 |
| abstractText | 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 (STAT3mut ) or a loss-of-function mutation in ERBB2IP (ERBB2IPmut ) 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-4Ralpha expression on naive lymphocytes and can induce expression and activation of the IL-4/IL-4Ralpha/GATA3 axis in vitro. These findings link increased TGF-beta pathway activation in ERBB2IPmut and STAT3mut patient lymphocytes with increased T helper type 2 cytokine expression and elevated IgE. |
