Nestin promotes pulmonary fibrosis via facilitating recycling of TGF-β receptor I.
Nestin promotes pulmonary fibrosis via facilitating recycling of TGF-β receptor I.
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Nestin 通过促进 TGF-β 受体 I 的再循环促进肺纤维化。
DOI：
10.1183/13993003.03721-2020
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发表时间：
2022-05
影响因子：
24.3
通讯作者：
Xiang, Andy Peng
中科院分区：
文献类型：
--
作者：
Wang, Jiancheng;Lai, Xiaofan;Yao, Senyu;Chen, Hainan;Cai, Jianye;Luo, Yulong;Wang, Yi;Qiu, Yuan;Huang, Yinong;Wei, Xiaoyue;Wang, Boyan;Lu, Qiying;Guan, Yuanjun;Wang, Tao;Li, Shiyue;Xiang, Andy Peng
特发性肺纤维化（IPF）是一种进行性纤维化肺病，其特征在于活化的肌成纤维细胞的异常增殖和细胞外基质的病理性重塑。以往的研究表明，中间丝蛋白巢蛋白在不同器官的组织再生和创伤愈合中起着关键作用。巢蛋白是否在IPF的发病机制中起关键作用需要澄清。测定博来霉素治疗的小鼠和IPF患者的肺组织中巢蛋白的表达。用调节转录生长因子（TGF）-β/Smad信号传导的巢蛋白短发夹RNA载体进行体外转染。用生物素标记法观察细胞膜TβRI、TβRI内吞和nestin敲低后TβRI再循环。在体内评估腺相关病毒血清型（AAV）6介导的巢蛋白敲低。我们发现巢蛋白表达在小鼠肺纤维化模型和IPF患者中增加，并且上调的蛋白质主要定位于肺α-平滑肌肌动蛋白阳性肌成纤维细胞。从机制上讲，我们确定nestin敲低通过抑制TβRI向细胞表面的再循环来抑制TGF-β信号传导，并且Rab 11是nestin促进TβRI再循环的能力所必需的。在体内，我们发现在多种实验小鼠模型中，肺内施用AAV 6介导的巢蛋白敲低显著减轻肺纤维化。我们的研究结果揭示了巢蛋白部分通过促进Rab 11依赖的TβRI再循环而发挥促纤维化作用，并为肺纤维化的治疗提供了新的思路。巢蛋白通过促进Rab 11依赖的TβRI再循环来调节囊泡运输系统，从而促进肺纤维化的进展。巢蛋白的精确靶向可能代表IPF的潜在治疗策略。https://bit.ly/3zO75c3
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that is characterised by aberrant proliferation of activated myofibroblasts and pathological remodelling of the extracellular matrix. Previous studies have revealed that the intermediate filament protein nestin plays key roles in tissue regeneration and wound healing in different organs. Whether nestin plays a critical role in the pathogenesis of IPF needs to be clarified. Nestin expression in lung tissues from bleomycin-treated mice and IPF patients was determined. Transfection with nestin short hairpin RNA vectors in vitro that regulated transcription growth factor (TGF)-β/Smad signalling was conducted. Biotinylation assays to observe plasma membrane TβRI, TβRI endocytosis and TβRI recycling after nestin knockdown were performed. Adeno-associated virus serotype (AAV)6-mediated nestin knockdown was assessed in vivo. We found that nestin expression was increased in a murine pulmonary fibrosis model and IPF patients, and that the upregulated protein primarily localised in lung α-smooth muscle actin-positive myofibroblasts. Mechanistically, we determined that nestin knockdown inhibited TGF-β signalling by suppressing recycling of TβRI to the cell surface and that Rab11 was required for the ability of nestin to promote TβRI recycling. In vivo, we found that intratracheal administration of AAV6-mediated nestin knockdown significantly alleviated pulmonary fibrosis in multiple experimental mice models. Our findings reveal a pro-fibrotic function of nestin partially through facilitating Rab11-dependent recycling of TβRI and shed new light on pulmonary fibrosis treatment. Nestin regulates the vesicular trafficking system by promoting Rab11-dependent recycling of TβRI and thereby contributes to the progression of pulmonary fibrosis. Precise targeting of nestin may represent a potential therapeutic strategy for IPF. https://bit.ly/3zO75c3
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DOI：
10.1016/j.jaci.2018.08.023
发表时间：
2019-04
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
Ke X;Do DC;Li C;Zhao Y;Kollarik M;Fu Q;Wan M;Gao P
通讯作者：
Gao P
DOI：
10.1164/rccm.201403-0509pp
发表时间：
2014-10-15
影响因子：
24.7
作者：
Ahluwalia, Neil;Shea, Barry S.;Tager, Andrew M.
通讯作者：
Tager, Andrew M.
影响因子：
5.6
作者：
Beguin, Pauline C.;Gosselin, Hugues;Calderone, Angelino
通讯作者：
Calderone, Angelino
从受体到 Smads 的 TGF-β 信号传导
影响因子：
7.2
作者：
Hata A;Chen YG
通讯作者：
Chen YG
影响因子：
7.4
作者：
Liu, Rui-Ming;Vayalil, Praveen Kumar;Ballinger, Carol;Dickinson, Dale A.;Huang, Wen-Tan;Wang, Suqing;Kavanagh, Terrance J.;Matthews, Qiana L.;Postlethwait, Edward M.
通讯作者：
Postlethwait, Edward M.