LncRNA GACAT2 binds with protein PKM1/2 to regulate cell mitochondrial function and cementogenesis in an inflammatory environment.
LncRNA GACAT2 binds with protein PKM1/2 to regulate cell mitochondrial function and cementogenesis in an inflammatory environment.
复制标题
DOI：
10.1038/s41413-022-00197-x
复制
发表时间：
2022-03-16
期刊：
影响因子：
12.7
通讯作者：
Chen FM
中科院分区：
文献类型：
--
作者：
Li X;Tian BM;Deng DK;Liu F;Zhou H;Kong DQ;Qu HL;Sun LJ;He XT;Chen FM
牙周膜干细胞（periodicalligament stem cells，PDLSCs）是修复/再生牙周组织（包括牙槽骨、牙周膜和牙根牙骨质）的关键细胞类型，牙根牙骨质对于恢复牙齿功能非常重要。然而，驻留在炎症环境中的PDLSC通常表现出受损的功能，如分化成成牙骨质细胞的能力受损所证明的，成牙骨质细胞负责牙骨质的再生。本研究探讨了线粒体功能和下游长链非编码RNA（lncRNA）在调节炎症诱导的PDLSC牙骨质形成变化中的作用。我们发现，炎症性尼古丁诱导的PDLSC的牙骨质形成损伤与其线粒体功能密切相关，并且lncRNA微阵列分析和功能获得/丧失研究将GACAT 2鉴定为参与炎症介导的线粒体功能和牙骨质形成的细胞事件的调节剂。随后，通过质谱（ChIRP-MS）和平行反应监测（PRM）测定对RNA结合蛋白进行了全面鉴定，结果显示GACAT 2可以直接结合丙酮酸激酶M1/2（PKM 1/2），这是一种与线粒体功能相关的蛋白质。进一步的功能研究表明，GACAT 2过表达增加了PKM 1/2、PKM 2四聚体和磷酸化PKM 2的细胞蛋白表达，这导致丙酮酸激酶（PK）活性增强和PKM 2向线粒体的易位增加。然后我们发现GACAT 2过表达可以逆转炎症诱导的PDLSC线粒体功能和成牙骨质细胞分化的损伤，并且这种作用可以通过PKM 1/2敲低而消除。我们的数据表明，通过结合PKM 1/2蛋白，lncRNA GACAT 2在炎症环境中调节线粒体功能和牙骨质形成中起关键作用。
Periodontal ligament stem cells (PDLSCs) are a key cell type for restoring/regenerating lost/damaged periodontal tissues, including alveolar bone, periodontal ligament and root cementum, the latter of which is important for regaining tooth function. However, PDLSCs residing in an inflammatory environment generally exhibit compromised functions, as demonstrated by an impaired ability to differentiate into cementoblasts, which are responsible for regrowing the cementum. This study investigated the role of mitochondrial function and downstream long noncoding RNAs (lncRNAs) in regulating inflammation-induced changes in the cementogenesis of PDLSCs. We found that the inflammatory cytokine-induced impairment of the cementogenesis of PDLSCs was closely correlated with their mitochondrial function, and lncRNA microarray analysis and gain/loss-of-function studies identified GACAT2 as a regulator of the cellular events involved in inflammation-mediated mitochondrial function and cementogenesis. Subsequently, a comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS) and parallel reaction monitoring (PRM) assays revealed that GACAT2 could directly bind to pyruvate kinase M1/2 (PKM1/2), a protein correlated with mitochondrial function. Further functional studies demonstrated that GACAT2 overexpression increased the cellular protein expression of PKM1/2, the PKM2 tetramer and phosphorylated PKM2, which led to enhanced pyruvate kinase (PK) activity and increased translocation of PKM2 into mitochondria. We then found that GACAT2 overexpression could reverse the damage to mitochondrial function and cementoblastic differentiation of PDLSCs induced by inflammation and that this effect could be abolished by PKM1/2 knockdown. Our data indicated that by binding to PKM1/2 proteins, the lncRNA GACAT2 plays a critical role in regulating mitochondrial function and cementogenesis in an inflammatory environment.
登录
查看更多内容
β-肌动蛋白的丧失会导致成骨重编程过程中成骨细胞分化基因的加速矿化和失调。
DOI：
10.1002/advs.202002261
发表时间：
2020-12
期刊：
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
影响因子：
--
作者：
Gjorgjieva T;Xie X;Commins P;Pasricha R;Mahmood SR;Gunsalus KC;Naumov P;Percipalle P
通讯作者：
Percipalle P
影响因子：
4.1
作者：
Ao M;Chavez MB;Chu EY;Hemstreet KC;Yin Y;Yadav MC;Millán JL;Fisher LW;Goldberg HA;Somerman MJ;Foster BL
通讯作者：
Foster BL
影响因子：
11.4
作者：
Chowdhury, Anindya Roy;Zielonka, Jacek;Avadhani, Narayan G.
通讯作者：
Avadhani, Narayan G.
影响因子：
4.1
作者：
DErrico, JA;Macneil, RL;Somerman, MJ
通讯作者：
Somerman, MJ
影响因子：
12.4
作者：
Han, Mingli;Qian, Xueke;Dong, Huaying
通讯作者：
Dong, Huaying