更新于：2024-09-19

OTUD3

更新于：2024-09-19

基本信息

别名

DUBA4、KIAA0459、OTU deubiquitinase 3

+ [2]

简介

Deubiquitinating enzyme that hydrolyzes 'Lys-6'- and 'Lys-11'-linked polyubiquitin. Also hydrolyzes heterotypic (mixed and branched) and homotypic chains (PubMed:23827681, PubMed:32011234, PubMed:35675826). Important regulator of energy metabolism (PubMed:35675826). Glucose and fatty acids trigger its nuclear translocation by CBP-dependent acetylation (PubMed:35675826). In the nucleus, deubiquitinates and stabilizes the nuclear receptor PPARD regulating the expression of various genes involved in glucose and lipid metabolism and oxidative phosphorylation (PubMed:35675826). Also acts as a negative regulator of the ribosome quality control (RQC) by mediating deubiquitination of 40S ribosomal proteins RPS10/eS10 and RPS20/uS10, thereby antagonizing ZNF598-mediated 40S ubiquitination (PubMed:32011234).

关联

项与 OTUD3 相关的药物

OTUDin3

靶点

OTUD3

作用机制

OTUD3 抑制剂

在研机构

中国人民解放军总医院

原研机构

中国人民解放军总医院

在研适应症

非小细胞肺癌

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 OTUD3 相关的临床结果

登录后查看更多信息

100 项与 OTUD3 相关的转化医学

登录后查看更多信息

0 项与 OTUD3 相关的专利（医药）

登录后查看更多信息

项与 OTUD3 相关的文献（医药）

2024-07-01·Cell Reports

Deubiquitylase OTUD3 regulates integrated stress response to suppress progression and sorafenib resistance of liver cancer

Article

作者: Zhang, Lingqiang ; Zhou, Lijie ; Ge, Yingwei ; Hong, Ruolin ; Zhang, Yuting ; Wu, Bo ; Zhang, Jinhao ; Hao, Yang ; Jiang, Wenli ; Li, Hongchang ; Dai, Hongmiao

The integrated stress response (ISR) is activated in response to intrinsic and extrinsic stimuli, playing a role in tumor progression and drug resistance. The regulatory role and mechanism of ISR in liver cancer, however, remain largely unexplored. Here, we demonstrate that OTU domain-containing protein 3 (OTUD3) is a deubiquitylase of eukaryotic initiation factor 2α (eIF2α), antagonizing ISR and suppressing liver cancer. OTUD3 decreases interactions between eIF2α and the kinase EIF2ΑK3 by removing K27-linked polyubiquitylation on eIF2α. OTUD3 deficiency in mice leads to enhanced ISR and accelerated progression of N-nitrosodiethylamine-induced hepatocellular carcinoma. Additionally, decreased OTUD3 expression associated with elevated eIF2α phosphorylation correlates with the progression of human liver cancer. Moreover, ISR activation due to decreased OTUD3 expression renders liver cancer cells resistant to sorafenib, while the combined use of the ISR inhibitor ISRIB significantly improves their sensitivity to sorafenib. Collectively, these findings illuminate the regulatory mechanism of ISR in liver cancer and provide a potential strategy to counteract sorafenib resistance.

2024-01-01·Journal of Cancer Research and Clinical Oncology

Immunogenic profiling of metastatic uveal melanoma discerns a potential signature related to prognosis

Article

作者: Wang, Jian ; Liu, Miaomiao ; Sun, Jiaxing ; Zhang, Zifeng

AbstractBackgroundUveal melanoma (UM) is an aggressive intraocular malignant tumor. The present study aimed to identify the key genes associated with UM metastasis and established a gene signature to analyze the relationship between the signature and prognosis and immune cell infiltration. Later, a predictive model combined with clinical variables was developed and validated.MethodsTwo UM gene expression profile chip datasets were downloaded from TCGA and GEO databases. Immune-related genes (IRGs) were obtained from IMPORT database. First, these mRNAs were intersected with IRGs, and weighted gene co-expression network analysis (WGCNA) was used to identify the co-expression of genes primarily associated with metastasis of UM. Univariate Cox regression analysis screened the genes related to prognosis. LASSO-Cox established a risk score to distinguish high-risk group and low-risk group. Then the GSEA enrichment pathway and immune cell infiltration of the two groups were compared. And combined with clinical variables, a predictive model was constructed. The time-dependent receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) curve were used to verify the stability and accuracy of the final predictive model, and a nomogram was then drawn.ResultsThe MEblack, MEpurple, and MEblue modules were significantly associated with the metastasis of UM patients (P value < 0.001, = 0.001, = 0.022, respectively). Four genes (UBXN2B, OTUD3, KAT8, LAMTOR2) were obtained by Pearson correlation analysis, weighted gene correlation network analysis (WGCNA), univariate Cox, and LASSO-Cox. And a novel prognostic risk score was established. Immune-related prognostic signature can well classify UM patients into high-risk and low-risk groups. Kaplan–Meier curve showed that the OS of high-risk patients was worse than that of low-risk patients. In addition, the risk score played an important role in evaluating the signaling pathway and immune cell infiltration of UM patients in high-risk and low-risk groups. Both the training set and validation set of the model showed good predictive accuracy in the degree of differentiation and calibration (e.g., 1-year overall survival: AUC = 0.930 (0.857–1.003)). Finally, a nomogram was established to serve in clinical practice.SignificanceUM key gene signature and prognosis predictive model might provide insights for further investigation of the pathogenesis and development of UM at the molecular level, and provide theoretical basis for determining new prognostic markers of UM and immunotherapy.

2023-11-01·Immunological investigations

Bone Marrow Stromal Cell-Secreted Extracellular Vesicles Containing miR-34c-5p Alleviate Lung Injury and Inflammation in Bronchopulmonary Dysplasia Through Promotion of PTEN Degradation by Targeting OTUD3.

Article

作者: Wang, Yijing ; Lan, Guofeng ; He, Xiao ; Kuang, Juan ; Shi, Xuekai

BACKGROUNDBronchopulmonary dysplasia (BPD) is the predominant chronic disorder in preterm neonates. This study explored impacts of miR-34c-5p carried by bone marrow stromal cells-secreted extracellular vesicles (BMSC-EVs) on BPD progression.METHODSA BPD mouse model was established, followed by measurement of miR-34c-5p, OTUD3, and PTEN expression. EVs were isolated from BMSCs transfected with miR-34c-5p mimic or mimic NC and intratracheally injected into mice. CD31 and Ki67 expression was detected and the pathological changes of lung tissues and lung function indexes were observed for mice. A neonatal human pulmonary microvascular endothelial cell (HPMEC) model was developed with hyperoxia, followed by co-culture with extracted EVs and ectopic experiments for measurement of cell viability, migration, and angiogenesis. IL-4, IL-13, IL-1β, and IL-6 levels were measured in cell supernatants and lung tissues. Dual-luciferase reporter, ubiquitination, Co-IP, and RIP assays were adopted to determine the relationship among miR-34c-5p, OTUD3, and PTEN.RESULTSLung tissues of BPD mice had downregulated miR-34c-5p expression and upregulated OTUD3 and PTEN expression. BMSC-EVs and BMSC-EVs-miR-34c-5p treatment improved lung injury and alveolar structure, decreased lung resistance and IL-4, IL-13, IL-1β, and IL-6 levels, and elevated dynamic lung compliance in BPD mice, as well as enhanced proliferation, angiogenesis, and migration and restrained inflammation in HPMECs. Mechanistically, miR-34c-5p negatively targeted OTUD3 which restrained ubiquitination to promote PTEN protein stabilization. Upregulation of OTUD3 or PTEN negated the changes in the proliferation, angiogenesis, migration, and inflammation of hyperoxia-treated HPMECs induced by BMSC-EVs-miR-34c-5p.CONCLUSIONBMSC-EVs-miR-34c-5p alleviated lung injury and inflammation in hyperoxia-induced BPD by blocking the OTUD3/PTEN axis.

项与 OTUD3 相关的新闻（医药）

2022-06-10

·中国生物技术网

Cell子刊：北京大学尹玉新等团队发现糖脂代谢调控的新体系

糖尿病影响全球超过 4 亿人，是一个巨大的公共卫生负担。肥胖是糖尿病患病的主要风险因素，会导致通常在糖尿病之前出现的胰岛素抵抗。目前，全基因组关联研究 (GWAS) 已经确定了80 多个糖尿病易感位点，而且已经在单基因形式的糖尿病中发现了越来越多的突变和变体，例如，青年成人型糖尿病 (MODY) 样糖尿病等。确定糖尿病的遗传因素有助于增进对这种疾病的病因和发病机制的认识，可以对早期预防及对症干预治疗提供强有力的支持。泛素-蛋白酶体依赖的蛋白质降解过程是调控细胞内蛋白质水平的主要途径。该过程由泛素连接酶介导的底物蛋白泛素化和去泛素化酶介导的底物蛋白去泛素化调控，蛋白质的泛素化和去泛素化过程构成蛋白质新陈代谢的动态平衡。目前已经鉴定出的泛素连接酶有1000多种，然而去泛素化酶只有100多种，提示每个去泛素化酶有着广谱的底物，参与多种生命过程。在既往研究中，已报道去泛素化酶OTU家族蛋白在肿瘤细胞凋亡与耐药中起关键作用，然而对其在能量代谢中的作用尚不清楚。2022年6月7日，北大-清华生命科学联合中心、北京大学尹玉新教授团队和山东第一医科大学附属省立医院宋勇峰教授团队合作在Cell Metabolism发表了题为Deubiquitinase OTUD3 regulates metabolism homeostasis in response to nutritional stresses的研究论文，揭示了去泛素酶体系统感知葡萄糖和脂肪酸等代谢信号，调控能量代谢的新机制。该研究阐述了去泛素化酶OTUD3动态传递葡萄糖/脂肪酸等代谢信号入核并维持能量代谢稳态的过程，其研究成果可为肥胖和糖尿病发病机理研究提供方向性指导，为制定有效预防和治疗措施提供理论依据。研究团队发现一个具有类似青少年发病的成人型糖尿病 (MODY) 特征的糖尿病家系，但基因组全外显子测序没有检出已知与MODY相关的致病基因突变，提示该家系可能由新的致病基因引起。进一步研究发现该家系中糖尿病患者携带OTUD3 c.863G>A突变，其编码蛋白OTUD3是OTU去泛素化酶家族成员。实验研究发现OTUD3 c.863G>A突变可以大幅降低OTUD3的去泛素化酶活性以及蛋白自身稳定性。为证明该基因是否与MODY遗传性糖尿病发病相关，团队构建了Otud3基因敲除小鼠，研究显示Otud3基因敲除小鼠出现代谢紊乱及高脂饮食诱导的肥胖形成胰岛素抵抗等糖尿病早期特征，表明OTUD3的去泛素化酶功能缺失会引起肥胖并增加糖尿病发生风险。进一步研究证实，OTUD3可感知机体的能量状态，动态调整在细胞质和细胞核中的分布，进而维持能量平衡，从而抑制肥胖发生。机制探索表明，在葡萄糖或脂肪酸刺激下，乙酰转移酶CBP感知糖脂代谢产生的乙酰辅酶A将OTUD3乙酰化，促使OTUD3转运入细胞核，切除以PPARδ为代表的多种与能量代谢相关的转录因子的泛素链，减缓这些转录因子的降解，延长其发挥功效的时间，以此维持细胞能量代谢的活性。然而当OTUD3功能出现障碍时，以PPARδ为代表的多种与能量代谢相关的转录因子的稳定性降低，难以维持细胞正常的能量代谢，进而导致肥胖、糖尿病发生。此外，该团队还通过CHIP-Seq联合RNA-Seq实验鉴定了OTUD3可能调控的转录因子，验证了去泛素化酶调控多个具有类似功能的底物并发挥强大的功能。同时将经典的去泛素化酶调控底物蛋白的稳定性拓宽到基因调控层面。综上所述，这项研究发现新的与肥胖及糖尿病发病相关的关键致病基因OTUD3，揭示了OTUD3蛋白功能相关的新的能量代谢调控机制，为寻找肥胖及糖尿病的潜在治疗靶点提供了新的线索。原文链接：https://doi-org.libproxy1.nus.edu.sg/10.1016/j.cmet.2022.05.005