Department of Pathology and Laboratory Medicine, Tulane, Wenbo University School of Medicine, New Orleans, Louisiana, United States of America.
PLoS One. 2020 Jan 29;15(1):e0228160. doi: 10.1371/journal.pone.0228160. eCollection 2020.
Recent studies have demonstrated the implication of long noncoding RNAs (lncRNAs) in a variety of physiological and pathological processes. However, the majority of lncRNAs are functionally unknown. The current study describes that the lncRNA MALAT1 regulates TGF-β/Smad signaling pathway through formation of a lncRNA-protein complex containing Smads, SETD2 and PPM1A. Our data show that this lncRNA-proteins complex facilitates the dephosphorylation of pSmad2/3 by providing the interaction niche for pSmad2/3 and their specific phosphatase PPM1A, thus terminating TGF-β/Smad signaling in hepatic cells. Based on these mechanistic studies, we performed further experiments to determine whether depletion of MALAT1 would augment cellular TGF-β/Smad signaling. We observed that MALAT1 depletion enhanced TGF-β/Smad signaling response, as reflect by amplification of Smad-mediated differentiation of induced pluripotent stem (iPS) cells to hepatocytes. Our experimental results demonstrate an important role of MALAT1 for regulation of TGF-β/Smad signaling in hepatic cells. Given the diverse functions of TGF-β/Smad pathway in various physiological and pathogenic processes, our results described in the current study will have broad implications for further understanding the role of MALAT1 in TGF-β/Smad pathway in human biology and disease.
最近的研究表明，长非编码 RNA（lncRNA）在多种生理和病理过程中具有重要作用。然而，大多数 lncRNA 的功能尚不清楚。本研究描述了 lncRNA MALAT1 通过形成包含 Smads、SETD2 和 PPM1A 的 lncRNA-蛋白复合物来调节 TGF-β/Smad 信号通路。我们的数据表明，这个 lncRNA-蛋白复合物通过为 pSmad2/3 及其特定的磷酸酶 PPM1A 提供相互作用的场所，促进 pSmad2/3 的去磷酸化，从而终止肝细胞中的 TGF-β/Smad 信号转导。基于这些机制研究，我们进一步进行了实验，以确定 MALAT1 的耗竭是否会增强细胞 TGF-β/Smad 信号。我们观察到 MALAT1 的耗竭增强了 TGF-β/Smad 信号反应，这反映在诱导多能干细胞（iPS 细胞）向肝细胞分化的 Smad 介导过程中得到了放大。我们的实验结果表明 MALAT1 在肝细胞中 TGF-β/Smad 信号转导的调节中起着重要作用。鉴于 TGF-β/Smad 通路在多种生理和病理过程中的广泛功能，我们在本研究中描述的结果将对进一步理解 MALAT1 在 TGF-β/Smad 通路中的作用在人类生物学和疾病中有广泛的意义。
