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Targeting deubiquitinase OTUB1 protects vascular smooth muscle cells in atherosclerosis by modulating PDGFR

《医学前沿（英文）》 2024年第18卷第3期页码 465-483 doi: 10.1007/s11684-024-1056-8

摘要： Atherosclerosis is a chronic artery disease that causes various types of cardiovascular dysfunction. Vascular smooth muscle cells (VSMCs), the main components of atherosclerotic plaque, switch from contractile to synthetic phenotypes during atherogenesis. Ubiquitylation is crucial in regulating VSMC phenotypes in atherosclerosis, and it can be reversely regulated by deubiquitinases. However, the specific effects of deubiquitinases on atherosclerosis have not been thoroughly elucidated. In this study, RNAi screening in human aortic smooth muscle cells was performed to explore the effects of OTU family deubiquitinases, which revealed that silencing OTUB1 inhibited PDGF-BB-stimulated VSMC phenotype switch. Further in vivo studies using Apoe^−/− mice revealed that knockdown of OTUB1 in VSMCs alleviated atherosclerosis plaque burden in the advanced stage and led to a stable plaque phenotype. Moreover, VSMC proliferation and migration upon PDGF-BB stimulation could be inhibited by silencing OTUB1 in vitro. Unbiased RNA-sequencing data indicated that knocking down OTUB1 influenced VSMC differentiation, adhesion, and proliferation. Mass spectrometry of ubiquitinated protein confirmed that proteins related to cell growth and migration were differentially ubiquitylated. Mechanistically, we found that OTUB1 recognized the K707 residue ubiquitylation of PDGFRβ with its catalytic triad, thereby reducing the K48-linked ubiquitylation of PDGFRβ. Inhibiting OTUB1 in VSMCs could promote PDGFRβ degradation via the ubiquitin–proteasome pathway, so it was beneficial in preventing VSMCs’ phenotype switch. These findings revealed that knocking down OTUB1 ameliorated VSMCs’ phenotype switch and atherosclerosis progression, indicating that OTUB1 could be a valuable translational therapeutic target in the future.

关键词： atherosclerosis vascular smooth muscle cell ubiquitylation deubiquitinase OTUB1 PDGFRβ

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时间序列多组学整合分析揭示原代肝细胞体外培养去分化过程伴随非降解性泛素化修饰的增加 Article

姜正一, 孙泽宇, 欧阳晓希, 赵亚磊, 周梦豪, 王保红, 李启睿, 范林骁, 张赛男, 李兰娟

《工程（英文）》 2020年第6卷第11期页码 1302-1314 doi: 10.1016/j.eng.2020.02.011

摘要：

目前，原代肝细胞（PHC）在各个研究领域被广泛使用，但是由于在体外培养过程中肝细胞特异性功能的迅速退化（即去分化），严重限制了它的应用范围。尽管学者已经对PHC的转录调控和全细胞蛋白质组（WCP）进行了广泛研究，但只有为数不多的研究考虑了蛋白质翻译后修饰（PTM）在这一过程中的作用。为了揭示引起PHC去分化的潜在机制，我们收集了在体外培养0 h、6 h、12 h、24 h和48 h的大鼠原代肝细胞样本，对各个时间点细胞样本的转录组、WCP、泛素化蛋白质组和磷酸化蛋白质组进行了定量分析。我们的数据包含了原代肝细胞体外培养去分化过程中详细的多组学分析结果，包括2196个蛋白质、2056个泛素化修饰位点和4932个磷酸化修饰位点。这项研究表明，PHC去分化过程中基因转录水平和蛋白质表达量之间的相关性较低。泛素化修饰组和对应的WCP联合分析表明，PHC去分化伴随着非降解性K27泛素化修饰位点的增加。对差异表达的磷酸化修饰蛋白进行功能富集分析，表明该过程中有铁死亡参与。其中，有404种蛋白质同时具有泛素化修饰位点和磷酸化修饰位点，被鉴定为与去分化事件有关的关键蛋白。最终，Ptbp1、Hnrpd、Hnrnpu和Srrm2被鉴定为PHC去分化过程中的hub分子。综上所述，我们的数据为抑制原代肝细胞体外培养去分化提供了潜在靶点分子及新的见解。

关键词：去分化原代肝细胞翻译后修饰泛素化蛋白质组学磷酸化蛋白质组学转录组学