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

作者：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 N; 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^*

来源：Journal of Experimental Medicine, 2017, 214(3): 669-680.

DOI：10.1084/jem.20161435

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.

• 出版日期2017-3
• 单位NIH