Dysregulation of TGF-β1 receptor activation leads to abnormal lung development and emphysema-like phenotype in core fucose-deficient mice
Dysregulation of TGF-β1 receptor activation leads to abnormal lung development and emphysema-like phenotype in core fucose-deficient mice
复制标题
DOI：
10.1073/pnas.0507375102
复制
发表时间：
2005-11-01
影响因子：
11.1
通讯作者：
Taniguchi, N
中科院分区：
文献类型：
--
作者：
Wang, XC;Inoue, S;Taniguchi, N
糖蛋白的核心岩藻糖基化（α 1，6-岩藻糖基化）广泛分布于哺乳动物组织中，并且在病理条件下发生改变。为了研究核心岩藻糖的生理功能，我们产生了α 1，6-岩藻糖基转移酶（Fut 8）-null小鼠，发现Fut 8的破坏在出生后发育期间诱导严重的生长迟缓和死亡。组织学分析显示，Fut 8（-1-）小鼠肺中显示肺气肿样变化，通过生理顺应性分析验证。生化研究表明，来自Fut 8 -1-小鼠的肺表现出与肺破坏性表型高度相关的基质金属蛋白酶（MMP）（如MMP-12和MMP-13）的显著过表达，以及细胞外基质（ECM）蛋白（如弹性蛋白）的下调，以及延迟的肺泡上皮细胞分化。这些变化应该与TGF-β 1信号传导的缺陷一致，TGF-β 1信号传导是一种通过下调MMP表达和诱导ECM蛋白组分来控制ECM稳态的多效性因子。事实上，根据TGF-β 1结合测定和Smad 2磷酸化分析的评估，Fut 8 -1小鼠对TGF-β 1受体激活和信号传导存在明显的失调。我们还表明，这些在Fut 8 -1-细胞中发现的TGF-β 1受体缺陷可以通过将Fut 8重新引入Fut 8（-/-）细胞来挽救。此外，外源性TGF-β 1可能挽救肺气肿样表型，并伴随着减少MMP表达Fut 8 -1-肺。我们认为TGF-β 1受体核心岩藻糖基化的缺乏对于发展性和进行性/破坏性肺气肿是至关重要的，这表明这种功能的扰动可能是某些人类肺气肿病例的基础。
The core fucosylation (alpha 1,6-fucosylation) of glycoproteins is widely distributed in mammalian tissues, and is altered under pathological conditions. To investigate physiological functions of the core fucose, we generated alpha 1,6-fucosyltransferase (Fut8)-null mice and found that disruption of Fut8 induces severe growth retardation and death during postnatal development. Histopathological analysis revealed that Fut8(-1-) mice showed emphysema-like changes in the lung, verified by a physiological compliance analysis. Biochemical studies indicated that lungs from Fut8-1- mice exhibit a marked overexpression of matrix metalloproteinases (MMPs), such as MMP-12 and MMP-13, highly associated with lung-destructive phenotypes, and a down-regulation of extracellular matrix (ECM) proteins such as elastin, as well as retarded alveolar epithelia cell differentiation. These changes should be consistent with a deficiency in TGF-beta 1 signaling, a pleiotropic factor that controls ECM homeostasis by down-regulating MMP expression and inducing ECM protein components. In fact, Fut8-1- mice have a marked dysregulation of TGF-beta 1 receptor activation and signaling, as assessed by TGF-beta 1 binding assays and Smad2 phosphorylation analysis. We also show that these TGF-beta 1 receptor defects found in Fut8-1- cells can be rescued by reintroducing Fut8 into Fut8(-/-)cells. Furthermore, exogenous TGF-beta 1 potentially rescued emphysema-like phenotype and concomitantly reduced MMP expression in Fut8-1- lung. We propose that the lack of core fucosylation of TGF-beta 1 receptors is crucial for a developmental and progressive/ destructive emphysema, suggesting that perturbation of this function could underlie certain cases of human emphysema.