Li Jiao, Zhou Jian-Kang, Mu Xiaoyu, Shen Shu, Xu Xiaomin, Luo Yao, Luo Yuxin, Ming Yue, Wu Yuangang, Peng Yong
Laboratory of Molecular Oncology Frontiers Science Center for Disease-related Molecular Network State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu China.
MedComm (2020). 2022 Apr 15;3(2):e125. doi: 10.1002/mco2.125. eCollection 2022 Jun.
Exportin 5 (XPO5) is a shuttle protein that mediates precursor miRNA (pre-miRNA) export from the nucleus to the cytoplasm, an important step in miRNA maturation. We previously demonstrated that XPO5 was phosphorylated by ERK kinase and subsequently underwent conformation change by the peptidyl-prolyl isomerase Pin1, leading to the reduced miRNA expression in hepatocellular carcinoma (HCC). Protein phosphorylation modification serves as a reversible regulatory mechanism precisely governed by protein kinases and phosphatases. Here we identified that the phosphatase PP2A catalyzed XPO5 dephosphorylation. PP2A holoenzyme is a ternary complex composed of a catalytic subunit, a scaffold subunit, and a regulatory subunit that determines substrate specificity. In this study, we characterized the involvement of B55β subunit in XPO5 dephosphorylation that favored the distribution of XPO5 into the cytoplasm and promoted miRNA expression, leading to HCC inhibition in vitro and in vivo. Our study demonstrates the regulatory role of B55β-containing PP2A in miRNA expression and may shed light on HCC pathogenesis.
输出蛋白5（XPO5）是一种穿梭蛋白，介导前体微小RNA（pre-miRNA）从细胞核输出到细胞质，这是微小RNA成熟过程中的重要一步。我们之前证明，XPO5被ERK激酶磷酸化，随后通过肽基脯氨酰异构酶Pin1发生构象变化，导致肝细胞癌（HCC）中微小RNA表达降低。蛋白质磷酸化修饰是一种由蛋白激酶和磷酸酶精确调控的可逆调节机制。在此，我们确定磷酸酶PP2A催化XPO5去磷酸化。PP2A全酶是一种三元复合物，由一个催化亚基、一个支架亚基和一个决定底物特异性的调节亚基组成。在本研究中，我们阐述了B55β亚基参与XPO5去磷酸化，这有利于XPO5在细胞质中的分布并促进微小RNA表达，从而在体外和体内抑制HCC。我们的研究证明了含B55β的PP2A在微小RNA表达中的调节作用，并可能为HCC发病机制提供线索。
