更新于：2024-11-01

JOSD2

更新于：2024-11-01

基本信息

别名

JOSD2、Josephin domain containing 2、Josephin domain-containing protein 2

+ [2]

简介

Cleaves 'Lys-63'-linked poly-ubiquitin chains, and with lesser efficiency 'Lys-48'-linked poly-ubiquitin chains (in vitro). May act as a deubiquitinating enzyme.

关联

项与 JOSD2 相关的药物

HY-041004

靶点

JOSD2

作用机制

JOSD2 inhibitors

在研机构

广州中医药大学 [+1]

原研机构

广州中医药大学 [+1]

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 JOSD2 相关的临床结果

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100 项与 JOSD2 相关的转化医学

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0 项与 JOSD2 相关的专利（医药）

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项与 JOSD2 相关的文献（医药）

2024-12-01·Cellular and Molecular Life Sciences

JOSD2 mediates isoprenaline-induced heart failure by deubiquitinating CaMKIIδ in cardiomyocytes

Article

作者: Liang, Guang ; Liang, Shiqi ; Zhou, Hao ; Wang, Qinyan ; Lou, Shuaijie ; Yu, Tianxiang ; Luo, Wu ; Qian, Jinfu ; Wang, Mengyang ; Zheng, Qingsong ; Xu, Jiachen

Prolonged stimulation of β-adrenergic receptor (β-AR) can lead to sympathetic overactivity that causes pathologic cardiac hypertrophy and fibrosis, ultimately resulting in heart failure. Recent studies suggest that abnormal protein ubiquitylation may contribute to the pathogenesis of cardiac hypertrophy and remodeling. In this study, we demonstrated that deficiency of a deubiquitinase, Josephin domain-containing protein 2 (JOSD2), ameliorated isoprenaline (ISO)- and myocardial infarction (MI)-induced cardiac hypertrophy, fibrosis, and dysfunction both in vitro and in vivo. Conversely, JOSD2 overexpression aggravated ISO-induced cardiac pathology. Through comprehensive mass spectrometry analysis, we identified that JOSD2 interacts with Calcium-calmodulin-dependent protein kinase II (CaMKIIδ). JOSD2 directly hydrolyzes the K63-linked polyubiquitin chains on CaMKIIδ, thereby increasing the phosphorylation of CaMKIIδ and resulting in calcium mishandling, hypertrophy, and fibrosis in cardiomyocytes. In vivo experiments showed that the cardiac remodeling induced by JOSD2 overexpression could be reversed by the CaMKIIδ inhibitor KN-93. In conclusion, our study highlights the role of JOSD2 in mediating ISO-induced cardiac remodeling through the regulation of CaMKIIδ ubiquitination, and suggests its potential as a therapeutic target for combating the disease. Please check and confirm that the authors and their respective affiliations have been correctly identified and amend if necessary. All have been checked.

2023-10-04·Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences

去泛素化酶JOSD2通过调控DNA损伤修复影响非小细胞肺癌细胞对抗肿瘤药物的敏感性.

Article

作者: Ge, Fujing ; Yang, Bo ; Yuan, Tao ; Zhu, Hong ; Liu, Xiangning ; He, Qiaojun ; Zhang, Hongyu

目的: 研究去泛素化酶含约瑟芬结构域2蛋白（JOSD2）对非小细胞肺癌（NSCLC）恶性进展的调控作用及其分子机制。方法: 从基因表达数据库下载NSCLC转录组表达数据及临床资料，利用主成分分析、limma差异分析和基因表达量分析考察NSCLC中表达水平显著上调的去泛素化酶相关基因；利用Kaplan-Meier生存分析算法考察不同去泛素化酶对NSCLC患者总生存期的影响；利用基因本体论富集分析和基因集富集分析考察高表达JOSD2的患者中信号通路的变化情况；利用基因集变异分析和皮尔逊相关性分析考察JOSD2表达水平与DNA损伤反应（DDR）通路的相关性；利用蛋白质印迹法考察JOSD2和DNA损伤修复通路相关蛋白的表达水平；利用免疫荧光和定量分析技术考察JOSD2在细胞内亚定位的变化；利用磺酰罗丹明染色法考察敲低JOSD2对DNA损伤类药物的敏感性。结果: 与癌旁组织比较，NSCLC组织中JOSD2的表达量显著上调（P<0.05），且与NSCLC患者的不良预后显著相关（P<0.05）；与低表达JOSD2的组织比较，高表达JOSD2的NSCLC组织中DDR相关途径显著激活（P<0.05），且JOSD2的表达水平与DDR相关途径激活程度呈显著正相关（P<0.01）；与对照组比较，过表达JOSD2显著促进NSCLC细胞系的DDR过程，此外，DNA损伤剂处理可显著提高JOSD2的细胞核定位，而敲低JOSD2显著增强NSCLC细胞对DNA损伤剂的敏感性（P<0.05）。结论: JOSD2通过促进DNA损伤修复途径调控NSCLC的恶性进展，而敲低JOSD2可显著增强NSCLC细胞对DNA损伤剂的敏感性。.

2023-02-01·Genes & Genomics

Deubiquitinating enzyme Josephin-2 stabilizes PHGDH to promote a cancer stem cell phenotype in hepatocellular carcinoma

Article

作者: Wang, Ying ; Shen, Wen-Long ; Li, Lu-Hao ; Li, Ze-Xin ; Wang, Jian-Guo ; Dang, Xiao-Wei

BACKGROUNDDeubiquitinating enzymes (DUBs) have been shown to be possible targets for hepatocellular carcinoma (HCC) treatment.OBJECTIVEThis study was designed to reveal the effect and underlying mechanism of Josephin-2, a relatively newly defined DUB, in HCC progression.METHODSSNU-387 and PLC/PRF/5 cells were used for in vitro functional assays. The levels of Josephin-2 and phosphoglycerate dehydrogenase (PHGDH) were determined using RT-qPCR and western blotting. Cell proliferation, migration and invasion were assessed by CCK-8, colony formation and Transwell. Spheroid-forming assay was performed to assess the cancer stem cell (CSC)-phenotype of HCC cells. A xenograft mice model was applied to verify the effect of Josephin-2 on HCC cell growth in vivo.RESULTSHerein, we showed that Josephin-2 expression was negatively correlated with HCC patient survival in data from the online database. Cell experiments indicated that knockdown of Josephin-2 attenuated HCC cell malignant biological behaviors. Besides, Josephin-2 silencing also decreased the spheroid-formation while inhibited the expression of CSC biomarkers (CD133, OCT4, SOX2 and EpCAM) in HCC cells. Mechanistically, Josephin-2 had a deubiquitinating activity towards the regulation of PHGDH protein, the rate-limiting enzyme in the first step of serine biosynthesis pathway. Depletion of Josephin-2 enhanced the ubiquitination degradation of PHGDH and ultimately inhibited the proliferation and CSC-phenotype of HCC in vitro and in vivo.CONCLUSIONOur work uncovered the regulatory effects of Josephin-2 on PHGDH protein stability and profiled its contribution in HCC malignant progression, which might provide a potential therapeutic target for HCC.

项与 JOSD2 相关的新闻（医药）

2023-08-24

·生物谷

Nature子刊 | 梁广/王怡课题组揭示去泛素化酶JOSD2保护心肌肥厚及心力衰竭新机制

心肌肥厚是伴随心力衰竭发生发展的重要病理生理过程。尽管目前的规范化药物治疗及器械辅助治疗改善了心力衰竭患者的临床症状，但其远期的心力衰竭再住院率和心血管死亡发生率仍处于较高水平。心肌细胞是终末分化细胞，再生能力差，因而维持心肌细胞内关键蛋白的稳定性对保护心肌细胞功能至关重要。从细胞内调控心肌细胞生理病理功能的关键蛋白入手，有望挖掘治疗心肌肥厚的新机制和新靶点具有重要的理论和转化意义。去泛素化酶（DUBs）可水解底物上的泛素分子来调控蛋白稳态。MJDs是DUBs中最小的亚家族，具有高度保守和真核广泛分布的特征。2023年8月7日，温州医科大学/杭州医学院梁广课题组在Nature子刊《Nature Cardiovascular Research》在线发表题为“Deubiquitinase JOSD2 improves calcium handling and attenuates cardiac hypertrophy and dysfunction through stabilizing SERCA2a in cardiomyocytes”的研究论文，揭示了MJDs去泛素化酶家族成员JOSD2调控心肌肥厚的作用、底物蛋白及分子机制。课题组首先鉴定出MJDs家族成员JOSD2成员是调控心肌肥厚的潜在候选蛋白；随后在体内水平，利用两种小鼠模型（TAC及Ang II）及蛋白功能缺失和获得技术（基因敲除及AAV9心肌特异性过表达），明确了JOSD2对小鼠心肌肥厚及心力衰竭的保护作用。利用多组学联合分析（泛素修饰组学、蛋白组学及蛋白互作组学），我们鉴定出SERCA2a（一种调节心肌细胞肌浆网钙离子再吸收的ATP泵）是心肌细胞JOSD2的关键底物并参与介导心肌肥厚。在机制上，JOSD2介导SERCA2a去泛素化，随后增强SERCA2a的蛋白稳定性。随后，通过调控SERCA2a，JOSD2参与介导心肌细胞的Ca2+ handling过程。我们的研究结果强调了JOSD2作为肥厚性心肌病保护性治疗靶点的前景，并为SERCA2a靶向治疗提供了新的策略。温州医科大学/杭州医学院梁广研究员和温州医科大学/杭州师范大学王怡研究员为该文章共同通讯作者；温州医科大学药学院为第一署名单位；温州医科大学药学院博士研究生韩集波和硕士研究生方子民为共同第一作者。该成果受到国家自然科学基金的支持。原文链接：https://www.nature.com/articles/s44161-023-00313-y会议推荐1大会信息会议名称 | 2023第六届单细胞多组学研究与临床应用研讨会会议时间 | 2023年9月14-15日会议地点 | 上海虹桥西郊丽笙大酒店大会规模 | 800人主办单位 | 生物谷扫码立即报名