近日,，美國生物化學(xué)雜志 Journal of Biological Chemistry在線發(fā)表了中科院上海生科院營養(yǎng)科學(xué)研究所陳雁研究組的最新研究成果Tollip, an intracellular trafficking protein, is a novel modulator of the transforming growth factor-beta signaling pathway ,。該研究發(fā)現(xiàn)一個接頭蛋白Tollip能與Smad7協(xié)同作用影響TGF-beta受體的泛素化降解過程，從而負調(diào)控TGF-beta信號通路,。
TGF-beta又稱轉(zhuǎn)化生長因子,，其信號通路在胚胎的早期發(fā)育,、免疫炎性反應(yīng)、腫瘤以及機體代謝平衡中都扮演著非常重要的角色。在機體內(nèi)TGF-beta信號通路的激活受到非常精確的調(diào)控,，研究其分子機制具有非常重要的基礎(chǔ)和應(yīng)用意義,。
陳雁研究員指導(dǎo)的博士研究生朱路和王玲娣等發(fā)現(xiàn)原本參與免疫反應(yīng)調(diào)控的接頭蛋白Tollip（Toll interacting protein）能與TGF-beta信號通路最主要的負調(diào)控因子Smad7相互作用，并與Smad7一起影響活化的TGF-beta受體在細胞中的轉(zhuǎn)運及泛素化降解過程,，從而負調(diào)控TGF-beta信號通路,。Tollip是新近發(fā)現(xiàn)的一種接頭蛋白，它廣泛表達于體內(nèi)各組織,。早期發(fā)現(xiàn)Tollip對Toll樣受體和白介素1受體所介導(dǎo)的信號通路的具有調(diào)控功能作,，并參與了白介素1受體在細胞中的轉(zhuǎn)運及泛素化降解過程。朱路等的研究證實Tollip也能夠與Smad7和TGF-beta受體相互作用,，而且這種相互作用和受體的泛素化相關(guān),。Smad7能有效地促進Tollip和TGF-beta受體之間的相互作用并增加他們在細胞中的共定位。另外,，Tollip可以加速TGF-beta受體的降解,。因此，這一研究表明Tollip和Smad7協(xié)同參與了TGF-beta受體細胞內(nèi)轉(zhuǎn)運和降解過程,，從而調(diào)控TGF-beta信號通路,，并提示Tollip可能成為TGF-beta信號通路與免疫細胞的信號通路相互作用的一個潛在媒介，并為以后的臨床相關(guān)研究提供了理論依據(jù),。
該課題獲得國家科技部,、國家自然科學(xué)基金委和中國科學(xué)院的資助。（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.
