BAT3 interacts with transforming growth factor-β (TGF-β) receptors and enhances TGF-β1-induced type I collagen expression in mesangial cells
BAT3 interacts with transforming growth factor-β (TGF-β) receptors and enhances TGF-β1-induced type I collagen expression in mesangial cells
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DOI：
10.1074/jbc.m802285200
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发表时间：
2008-07-11
影响因子：
4.8
通讯作者：
Choi, Mary E.
中科院分区：
文献类型：
--
作者：
Kwak, Joon Hyeok;Kim, Sung Il;Choi, Mary E.
转化生长因子-β 1（TGF-β 1）在广泛的细胞过程中起重要作用，例如在组织纤维化的发育和发病机制中，包括与进行性肾病相关的组织纤维化。其信号传导途径的严格调节是至关重要的，与TGF-β受体相关的蛋白质可能对TGF-β信号传导产生积极或消极的调节作用。在本研究中，我们采用了基于酵母的双杂交筛选系统，以确定BAT 3（HLA-B相关的转录本3）作为TGF-β受体相互作用蛋白。对包括肾脏在内的各种组织中内源性表达的BAT 3的分析揭示了存在类似于140 kDa全长蛋白以及其表达受发育调节的BAT 3的截短形式。内源性BAT 3蛋白与肾系膜细胞中TGF-β受体I型和II型相互作用。功能测定显示全长BAT 3的表达导致TGF-β 1刺激的p3 TP-Lux报告基因的转录激活增强，并且这些作用需要功能性TGF-β信号传导受体的存在，如在R-1B和DR-26突变细胞中所证明的。此外，全长BAT 3的表达，而不是BAT 3的C-末端截短突变体，增强TGF-β 1诱导的系膜细胞I型胶原的表达，而小干扰RNA敲低BAT 3蛋白表达抑制TGF-β 1诱导的I型胶原的表达。我们的研究结果表明，BAT 3，TGF-β受体相互作用蛋白，能够调节TGF-β信号转导，并作为一个积极的调节TGF-β 1刺激I型胶原蛋白在系膜细胞的表达。
Transforming growth factor-beta 1 (TGF-beta 1) plays essential roles in a wide array of cellular processes, such as in development and the pathogenesis of tissue fibrosis, including that associated with progressive kidney diseases. Tight regulation of its signaling pathways is critical, and proteins that associate with the TGF-beta receptors may exert positive or negative regulatory effects on TGF-beta signaling. In the present study we employed a yeast-based two-hybrid screening system to identify BAT3 (HLA-B-associated transcript 3) as a TGF-beta receptor-interacting protein. Analysis of endogenously expressed BAT3 in various tissues including the kidney reveals the existence of similar to 140kDa full-length protein as well as truncated forms of BAT3 whose expression is developmentally regulated. Endogenous BAT3 protein interacts with TGF-beta receptors type I and type II in renal mesangial cells. Functional assays show that expression of full-length BAT3 results in enhancement of TGF-beta 1-stimulated transcriptional activation of p3TP-Lux reporter, and these effects require the presence of functional TGF-beta signaling receptors as demonstrated in R-1B and DR-26 mutant cells. Moreover, expression of full-length BAT3, but not C-terminal truncated mutant of BAT3, enhanced TGF-beta 1-induced type I collagen expression in mesangial cells, whereas knock down of BAT3 protein expression by small interfering RNA suppressed the expression of type I collagen induced by TGF-beta 1. Our findings suggest that BAT3, a TGF-beta receptor-interacting protein, is capable of modulating TGF-beta signaling and acts as a positive regulator of TGF-beta 1 stimulation of type I collagen expression in mesangial cells.