A novel lncRNA ABCE1-5 regulates pulmonary fibrosis by targeting KRT14.

IF 5 2区 生物学 Q2 CELL BIOLOGY
Shuwei Gao, Yanqiu Wei, Chen Li, Bingbing Xie, Xinran Zhang, Ye Cui, Huaping Dai
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Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and degenerative interstitial lung disease characterized by complex etiology, unclear pathogenesis, and high mortality. Long non-coding RNAs (lncRNAs) have been identified as key regulators in modulating the initiation, maintenance, and progression of pulmonary fibrosis. However, the precise pathological mechanisms through which lncRNAs are involved in IPF remain limited and require further elucidation. A novel lncABCE1-5 was identified as significantly decreased by an ncRNA microarray analysis in our eight IPF lung samples compared with three donor tissues and validated by qRT-PCR analysis in clinical lung samples. To investigate the biological function of ABCE1-5, we performed loss-and gain-of-function experiments in vitro and in vivo. LncABCE1-5 silencing promoted A549 cell migration and A549 and BEAS-2B cell apoptosis, while enhancing the expression of proteins associated with extracellular matrix deposition, whereas overexpression of ABCE1-5 partially attenuated TGF-β-induced fibrogenesis. Forced ABCE1-5 expression by intratracheal injection of adeno-associated virus 6 (AAV6) revealing the anti-fibrotic effect of ABCE1-5 in BLM-treated mice. Mechanistically, RNA pull-down-mass spectrometry and RIP assay demonstrated that ABCE1-5 directly binds to keratin14 (krt14) sequences, potentially impeding its expression by perturbing mRNA stability. Furthermore, decreased ABCE1-5 levels can promote krt14 expression and enhance the phosphorylation of both mTOR and Akt; overexpression of ABCE1-5 in BLM mouse lung tissue significantly attenuated the elevated levels of p-mTOR and p-AKT. Knockdown of krt14 reversed the activation of mTOR signaling mediated by ABCE1-5 silencing. Collectively, the downregulation of ABCE1-5 mediated krt14 activation, thereby activating mTOR/AKT signaling, to facilitate pulmonary fibrosis progression in IPF.

一个新的lncRNA ABCE1-5通过靶向KRT14调控肺纤维化。
特发性肺纤维化(IPF)是一种进行性和退行性间质性肺疾病,其病因复杂,发病机制不明确,死亡率高。长链非编码rna (lncRNAs)已被确定为调节肺纤维化发生、维持和进展的关键调控因子。然而,lncrna参与IPF的确切病理机制仍然有限,需要进一步阐明。通过ncRNA微阵列分析,我们在8个IPF肺样本中发现了一种新的lncABCE1-5,与3个供体组织相比,其含量显著降低,并在临床肺样本中通过qRT-PCR分析进行了验证。为了研究ABCE1-5的生物学功能,我们在体外和体内进行了功能丧失和功能获得的实验。LncABCE1-5的沉默促进了A549细胞的迁移和A549和BEAS-2B细胞的凋亡,同时增强了细胞外基质沉积相关蛋白的表达,而ABCE1-5的过表达部分减弱了TGF-β诱导的纤维形成。通过气管内注射腺相关病毒6 (AAV6)强迫ABCE1-5表达,揭示ABCE1-5在blm处理小鼠中的抗纤维化作用。在机制上,RNA下拉质谱和RIP分析表明,ABCE1-5直接结合到角化蛋白14 (krt14)序列上,可能通过扰乱mRNA的稳定性来阻碍其表达。此外,ABCE1-5水平的降低可以促进krt14的表达,增强mTOR和Akt的磷酸化;ABCE1-5在BLM小鼠肺组织中过表达可显著降低p-mTOR和p-AKT的升高水平。krt14的敲低逆转了ABCE1-5沉默介导的mTOR信号的激活。总的来说,ABCE1-5的下调介导了krt14的激活,从而激活了mTOR/AKT信号,促进了IPF中肺纤维化的进展。
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来源期刊
CiteScore
9.10
自引率
1.80%
发文量
252
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Cell Physiology is dedicated to innovative approaches to the study of cell and molecular physiology. Contributions that use cellular and molecular approaches to shed light on mechanisms of physiological control at higher levels of organization also appear regularly. Manuscripts dealing with the structure and function of cell membranes, contractile systems, cellular organelles, and membrane channels, transporters, and pumps are encouraged. Studies dealing with integrated regulation of cellular function, including mechanisms of signal transduction, development, gene expression, cell-to-cell interactions, and the cell physiology of pathophysiological states, are also eagerly sought. Interdisciplinary studies that apply the approaches of biochemistry, biophysics, molecular biology, morphology, and immunology to the determination of new principles in cell physiology are especially welcome.
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