ERBIN deficiency links STAT3 and TGF-β pathway defects with atopy in humans.
ERBIN deficiency links STAT3 and TGF-β pathway defects with atopy in humans.
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DOI：
10.1084/jem.20161435
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发表时间：
2017-03-06
期刊：
影响因子：
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通讯作者：
Milner JD
中科院分区：
文献类型：
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作者：
Lyons JJ;Liu Y;Ma CA;Yu X;O'Connell MP;Lawrence MG;Zhang Y;Karpe K;Zhao M;Siegel AM;Stone KD;Nelson C;Jones N;DiMaggio T;Darnell DN;Mendoza-Caamal E;Orozco L;Hughes JD;McElwee J;Hohman RJ;Frischmeyer-Guerrerio PA;Rothenberg ME;Freeman AF;Holland SM;Milner JD
里昂等人表明，STAT 3通过ERBIN负调节TGF-β信号传导，TGF-β途径活化的细胞内在失调促进IL-4/IL-4 R α/GATA 3轴，以支持人类的特应性表型。人类的非免疫性结缔组织表型在一些先天性和获得性过敏性疾病中很常见。这些先天性疾病中有几种与TGF-β活性增加或STAT 3活化受损有关，表明这些途径可能交叉，它们的破坏可能导致特应性。在这项研究中，我们发现STAT 3通过ERBB 2相互作用蛋白（ERBIN）负调控TGF-β信号传导，ERBIN是SMAD受体激活的锚和SMAD 2/3结合蛋白。具有显性负性STAT 3突变（STAT 3 mut）或ERBB 2 IP功能丧失突变（ERBB 2 IPmut）的个体有证据表明TGF-β信号转导失调，调节性T细胞和总FOXP 3表达增加。在体外重现的这些天然存在的突变损害了STAT 3-ERBIN-SMAD 2/3复合物的形成，并且不能抑制细胞核pSMAD 2/3对TGF-β的应答。反过来，TGF-β信号传导的细胞内在失调与幼稚淋巴细胞上功能性IL-4 R α表达增加相关，并可在体外诱导IL-4/IL-4 R α/GATA 3轴的表达和活化。这些发现将ERBB 2 IPmut和STAT 3 mut患者淋巴细胞中TGF-β途径活化增加与辅助性T细胞2型细胞因子表达增加和IgE升高联系起来。
Lyons et al. show that STAT3 negatively regulates TGF-β signaling via ERBIN and that cell-intrinsic deregulation of TGF-β pathway activation promotes the IL-4/IL-4Rα/GATA3 axis to support atopic phenotypes in humans. 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.