近日，美国生物化学杂志 Journal of Biological Chemistry在线发表了中科院上海生科院营养科学研究所陈雁研究组的最新研究成果Tollip, an intracellular trafficking protein, is a novel modulator of the transforming growth factor-beta signaling pathway 。该研究发现一个接头蛋白Tollip能与Smad7协同作用影响TGF-beta受体的泛素化降解过程，从而负调控TGF-beta信号通路。
TGF-beta又称转化生长因子，其信号通路在胚胎的早期发育、免疫炎性反应、肿瘤以及机体代谢平衡中都扮演着非常重要的角色。在机体内TGF-beta信号通路的激活受到非常精确的调控，研究其分子机制具有非常重要的基础和应用意义。
陈雁研究员指导的博士研究生朱路和王玲娣等发现原本参与免疫反应调控的接头蛋白Tollip（Toll interacting protein）能与TGF-beta信号通路最主要的负调控因子Smad7相互作用，并与Smad7一起影响活化的TGF-beta受体在细胞中的转运及泛素化降解过程，从而负调控TGF-beta信号通路。Tollip是新近发现的一种接头蛋白，它广泛表达于体内各组织。早期发现Tollip对Toll样受体和白介素1受体所介导的信号通路的具有调控功能作，并参与了白介素1受体在细胞中的转运及泛素化降解过程。朱路等的研究证实Tollip也能够与Smad7和TGF-beta受体相互作用，而且这种相互作用和受体的泛素化相关。Smad7能有效地促进Tollip和TGF-beta受体之间的相互作用并增加他们在细胞中的共定位。另外，Tollip可以加速TGF-beta受体的降解。因此，这一研究表明Tollip和Smad7协同参与了TGF-beta受体细胞内转运和降解过程，从而调控TGF-beta信号通路，并提示Tollip可能成为TGF-beta信号通路与免疫细胞的信号通路相互作用的一个潜在媒介，并为以后的临床相关研究提供了理论依据。
该课题获得国家科技部、国家自然科学基金委和中国科学院的资助。（生物谷Bioon.com）
doi: 10.1074/jbc.M112.388009
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Tollip, an intracellular trafficking protein, is a novel modulator of the transforming growth factor-beta signaling pathway
Zhu L, Wang L, Luo X, Zhang Y, Ding Q, Jiang X, Wang X, Pan Y, Chen Y.
Upon activation, TGFβ type I receptor (TβRI) undergoes active ubiquitination via recruitment of E3 ligases to the receptor complex by Smad7. However, how ubiquitination of TβRI is coupled to intracellular trafficking and protein degradation remains unclear. We report here that Tollip, an adaptor protein that contains both ubiquitin associated domains and endosome targeting domain, plays an important role in modulating trafficking and degradation of TβRI. Tollip was previously demonstrated to possess a functional role in modulating the signaling of interleukin-1 and Toll-like receptors. We identify here that Tollip interacts with Smad7, a major modulatory protein involved in the negative regulation of TGFβ signaling. Overexpression of Tollip antagonizes TGFβ stimulated transcriptional response, Smad2 phosphorylation and epithelial mesenchymal transition. Tollip also interacts with ubiquitinated TβRI and such interaction requires ubiquitin-associated domains of Tollip. The interaction and intracellular colocalization of Tollip with TβRI is enhanced by Smad7. Overexpression of Tollip accelerates protein degradation of activated TβRI. In addition, Tollip alters subcellular compartmentalization and endosomal trafficking of activated TβRI. Collectively, our studies reveal that Tollip cooperates with Smad7 to modulate intracellular trafficking and degradation of ubiquitinated TβRI, whereby negatively regulates TGFβ signaling pathway.
