SNX25 regulates TGF-β signaling by enhancing the receptor degradation
SNX25 regulates TGF-β signaling by enhancing the receptor degradation
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DOI：
10.1016/j.cellsig.2011.01.022
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发表时间：
2011-05-01
影响因子：
4.8
通讯作者：
Chang, Zhijie
中科院分区：
文献类型：
--
作者：
Hao, Xinbao;Wang, Yinyin;Chang, Zhijie
SNX（分选连接蛋白）是在内吞网络内的隔室的货物分选和信号传导中起作用的蛋白质家族，其调节包括TGF-β受体的膜蛋白的运输。在这里，我们报告全长人类和小鼠SNX 25，与PX，PXA和RGS结构域的SNX成员，共定位与TGF-β受体，并形成内化的细胞质斑点后，与TGF-β治疗。虽然SNX 25的过表达抑制TGF-β诱导的荧光素酶报告基因活性，但在NIH 3 T3细胞中通过siRNA敲低内源性SNX 25可提高TGF-β受体水平并促进TGF-β信号传导。免疫沉淀实验证明SNX 25与T β RI相互作用。Western印迹分析表明，SNX 25增强了TGF-β受体的降解。SNX 25诱导的TGF-β受体降解显示为通过网格蛋白依赖性内吞途径进入溶酶体。我们已经确定了SNX 25的PXA结构域是T β RI降解所必需的。我们的研究结果表明，SNX 25负调节TGF-β信号通过溶酶体途径增强受体降解。(C)2011 Elsevier Inc. All rights reserved.
SNXs (sorting nexin), a family of proteins playing roles in cargo sorting and signaling from compartments within the endocytic network, regulate traffic of membrane proteins including TGF-beta receptors. Here we report that the full length human and mouse SNX25, a SNX member with PX, PXA and RGS domains, colocalizes with TGF-beta receptors, and forms internalized cytosolic punctae upon treatment with TGF-beta. While overexpression of SNX25 inhibits TGF-beta induced luciferase reporter activity, knocking down endogenous SNX25 by siRNA in NIH3T3 cells elevates the TGF-beta receptor levels and facilitates TGF-beta signaling. Immunoprecipitation experiments demonstrate that SNX25 interacts with T beta RI. Western blot analyses indicate that SNX25 enhances the degradation of TGF-beta receptors. SNX25 induced TGF-beta receptor degradation is shown via the clathrin dependent endocytosis pathway into lysosome. We have characterized that PXA domain of SNX25 is required for the degradation of T beta RI. Our findings demonstrate that SNX25 negatively regulates TGF-beta signaling by enhancing the receptor degradation through lysosome pathway. (C) 2011 Elsevier Inc. All rights reserved.