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PLP2, a potent deubiquitinase from murine hepatitis virus, strongly inhibits cellular type I interferon production 被引量:20
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作者 Dahai Zheng Gang Chen +2 位作者 Beichu Guo Genhong Cheng Hong Tang 《Cell Research》 SCIE CAS CSCD 2008年第11期1105-1113,共9页
Infections by coronaviruses such as severe acute respiratory syndrome (SARS) coronavirus (SCoV) and mouse hepatitis virus A59 (MHV-A59) result in very little type I interferon (IFN) production by host cells, w... Infections by coronaviruses such as severe acute respiratory syndrome (SARS) coronavirus (SCoV) and mouse hepatitis virus A59 (MHV-A59) result in very little type I interferon (IFN) production by host cells, which is potentially responsible for the rapid viral growth and severe immunopathology associated with SARS. However, the molecular mechanisms for the low IFN production in cells infected with coronaviruses remain unclear. Here, we provide evidence that Papain-like protease domain 2 (PLP2), a catalytic domain of the nonstructural protein 3 (nsp3) of MHV-A59, can bind to IRF3, cause its deubiquitination and prevent its nuclear translocation. As a consequence, co-expression of PLP2 strongly inhibits CARDIF-, TBK1- and IRF3-mediated IFNp reporter activities. In addition, we show that wild-type PLP2 but not the mutant PLP2 lacking the deubiquitinase (DUB) activity can reduce IFN induction and promote viral growth in cells infected with VSV. Thus, our study uncovered a viral DUB which coronaviruses may use to escape from the host innate antiviral responses. 展开更多
关键词 MHV-A59 PLP2 deubiquitinATION IRF3 type I interferons
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Deubiquitinating enzyme regulation of the p53 pathway: A lesson from Otub1 被引量:10
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作者 Xiao-Xin Sun Mu-Shui Dai 《World Journal of Biological Chemistry》 CAS 2014年第2期75-84,共10页
Deubiquitination has emerged as an important mechanism of p53 regulation. A number of deubiquitinating enzymes(DUBs) from the ubiquitin-specific protease family have been shown to regulate the p53-MDM2-MDMX networks. ... Deubiquitination has emerged as an important mechanism of p53 regulation. A number of deubiquitinating enzymes(DUBs) from the ubiquitin-specific protease family have been shown to regulate the p53-MDM2-MDMX networks. We recently reported that Otub1, a DUB from the OTU-domain containing protease family, is a novel p53 regulator. Interestingly, Otub1 abrogates p53 ubiquitination and stabilizes and activates p53 in cells independently of its deubiquitinating enzyme activity. Instead, it does so by inhibiting the MDM2 cognate ubiquitin-conjugating enzyme(E2) UbcH5. Otub1 also regulates other biological signaling through this non-canonical mechanism, suppression of E2, including the inhibition of DNA-damage-induced chromatin ubiquitination. Thus, Otub1 evolves as a unique DUB that mainly suppresses E2 to regulate substrates. Here we review the current progress made towards the understanding of the complex regulation of the p53 tumor suppressor pathway by DUBs, the biological function of Otub1 including its positive regulation of p53, and the mechanistic insights into how Otub1 suppresses E2. 展开更多
关键词 p53 MDM2 UBIQUITINATION deubiquitinating ENZYMES Otub1 Cell CYCLE APOPTOSIS
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Deubiquitination complex platform:A plausible mechanism for regulating the substrate specificity of deubiquitinating enzymes 被引量:1
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作者 Yi-Zheng Fang Li Jiang +2 位作者 Qiaojun He Ji Cao Bo Yang 《Acta Pharmaceutica Sinica B》 SCIE CAS CSCD 2023年第7期2955-2962,共8页
Deubiquitinating enzymes(DUBs) or deubiquitinases facilitate the escape of multiple proteins from ubiquitin-proteasome degradation and are critical for regulating protein expression levels in vivo.Therefore,dissecting... Deubiquitinating enzymes(DUBs) or deubiquitinases facilitate the escape of multiple proteins from ubiquitin-proteasome degradation and are critical for regulating protein expression levels in vivo.Therefore,dissecting the underlying mechanism of DUB recognition is needed to advance the development of drugs related to DUB signaling pathways.To data,extensive studies on the ubiquitin chain specificity of DUBs have been reported,but substrate protein recognition is still not clearly understood.As a breakthrough,the scaffolding role may be significant to substrate protein selectivity.From this perspective,we systematically characterized the scaffolding proteins and complexes contributing to DUB substrate selectivity.Furthermore,we proposed a deubiquitination complex platform(DCP) as a potentially generic mechanism for DUB substrate recognition based on known examples,which might fill the gaps in the understanding of DUB substrate specificity. 展开更多
关键词 deubiquitinating enzyme(DUB) deubiquitinATION Substrate specificity COMPLEX SCAFFOLD Protein partner
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Deubiquitinase ubiquitin-specific protease 3 (USP3) inhibits HIV-1 replication via promoting APOBEC3G (A3G) expression in both enzyme activity-dependent and -independent manners 被引量:1
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作者 Simin Zhao Baisong Zheng +5 位作者 Liuli Wang Wenzhe Cui Chunlai Jiang Zhuo Li Wenying Gao Wenyan Zhang 《Chinese Medical Journal》 SCIE CAS CSCD 2022年第22期2706-2717,共12页
Background: Ubiquitination plays an essential role in many biological processes, including viral infection, and can be reversed by deubiquitinating enzymes (DUBs). Although some studies discovered that DUBs inhibit or... Background: Ubiquitination plays an essential role in many biological processes, including viral infection, and can be reversed by deubiquitinating enzymes (DUBs). Although some studies discovered that DUBs inhibit or enhance viral infection by various mechanisms, there is lack of information on the role of DUBs in virus regulation, which needs to be further investigated.Methods: Immunoblotting, real-time polymerase chain reaction,in vivo/in vitro deubiquitination, protein immunoprecipitation, immunofluorescence, and co-localization biological techniques were employed to examine the effect of ubiquitin-specific protease 3 (USP3) on APOBEC3G (A3G) stability and human immunodeficiency virus (HIV) replication. To analyse the relationship between USP3 and HIV disease progression, we recruited 20 HIV-infected patients to detect the levels of USP3 and A3G in peripheral blood and analysed their correlation with CD4^(+) T-cell counts. Correlation was estimated by Pearson correlation coefficients (for parametric data).Results: The results demonstrated that USP3 specifically inhibits HIV-1 replication in an A3G-dependent manner. Further investigation found that USP3 stabilized 90% to 95% of A3G expression by deubiquitinating Vif-mediated polyubiquitination and blocking its degradation in an enzyme-dependent manner. It also enhances the A3G messenger RNA (mRNA) level by binding to A3G mRNA and stabilizing it in an enzyme-independent manner. Moreover, USP3 expression was positively correlated with A3G expression (r= 0.5110) and CD4^(+) T-cell counts (r= 0.5083) in HIV-1-infected patients.Conclusions: USP3 restricts HIV-1 viral infections by increasing the expression of the antiviral factor A3G. Therefore, USP3 may be an important target for drug development and serve as a novel therapeutic strategy against viral infections. 展开更多
关键词 APOBEC3G Ubiquitin-specific protease 3 deubiquitinATION Human immunodeficiency virus-1 Vif Human immunodeficiency virus deubiquitinase
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;he regulation of TGF-β/SMAD signaling by protein deubiquitination 被引量:28
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作者 Juan Zhang Xiaofei Zhang +4 位作者 Feng Xie Zhengkui Zhang Hans van Dam Long Zhang Fangfang Zhou 《Protein & Cell》 SCIE CAS CSCD 2014年第7期503-517,共15页
Transforming growth factor-β (TGF-β) members are key cytokines that control embryogenesis and tissue homeostasis via transmembrane TGF-β type II (TβR II) and type I (TβRI) and serine/threonine kinases recep... Transforming growth factor-β (TGF-β) members are key cytokines that control embryogenesis and tissue homeostasis via transmembrane TGF-β type II (TβR II) and type I (TβRI) and serine/threonine kinases receptors. Aberrant activation of TGF-β signaling leads to diseases, including cancer. In advanced cancer, the TGF-β/SMAD pathway can act as an oncogenic factor driving tumor cell invasion and metastasis, and thus is considered to be a therapeutic target. The activity of TGF-β/SMAD pathway is known to be regulated by ubiquitination at multiple levels. As ubiquitination is reversible, emerging studies have uncovered key roles for ubiquitin-removals on TGF-β signaling components by deubiquitinating enzymes (DUBs). In this paper, we summarize the latest findings on the DUBs that control the activity of the TGF-β signaling pathway. The regula- tory roles of these DUBs as a driving force for cancer progression as well as their underlying working mech- anisms are also discussed. 展开更多
关键词 TGF-Β TΒRI SMAD DUB ubiquitin deubiquitination
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The role of ubiquitination and deubiquitination in the regulation of cell junctions 被引量:11
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作者 Junting Cai Miranda K. Culley +1 位作者 Yutong Zhao Jing Zhao 《Protein & Cell》 SCIE CAS CSCD 2018年第9期754-769,共16页
Maintenance of cell junctions plays a crucial role in the regulation of cellular functions including cell proliferation, permeability, and cell death. Disruption of cell junctions is implicated in a variety of human d... Maintenance of cell junctions plays a crucial role in the regulation of cellular functions including cell proliferation, permeability, and cell death. Disruption of cell junctions is implicated in a variety of human disorders, such as inflammatory diseases and cancers. Understanding molecular regulation of cell junctions is important for development of therapeutic strategies for intervention of human diseases. Ubiquitination is an important type of post-translational modification that primarily regulates endogenous protein stability, recep- tor internalization, enzyme activity, and protein-protein interactions. Ubiquitination is tightly regulated by ubiq- uitin E3 ligases and can be reversed by deubiquitinating enzymes. Recent studies have been focusing on inves- tigating the effect of protein stability in the regulation of cell-cell junctions. Ubiquitination and degradation of cadherins, claudins, and their interacting proteins are implicated in epithelial and endothelial barrier disruption. Recent studies have revealed that ubiquitination is involved in regulation of Rho GTPases' biological activities. Taken together these studies, ubiquitination plays a critical role in modulating cell junctions and motility. In this review, we will discuss the effects of ubiquitination and deubiquitination on protein stability and expression of key proteins in the cell-cell junctions, including junction proteins, their interacting proteins, and small Rho GTPases. We provide an overview of protein stability in modulation of epithelial and endothelial barrier integrity and introduce potential future search directions to better understand the effects of ubiquitination on human disorders caused by dysfunction of cell junctions. 展开更多
关键词 cell-cell junctions protein stability UBIQUITINATION deubiquitinATION Rho GTPases
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OTUD5 promotes innate antiviral and antitumor immunity through deubiquitinating and stabilizing STING 被引量:5
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作者 Yunyun Guo Fei Jiang +13 位作者 Lingli Kong Haifeng Wu Honghai Zhang Xiaorong Chen Jian Zhao Baoshan Cai Yanqi Li Chunhong Ma Fan Yi Lei Zhang Bingyu Liu Yi Zheng Lingqiang Zhang Chengjiang Gao 《Cellular & Molecular Immunology》 SCIE CAS CSCD 2021年第8期1945-1955,共11页
Stimulator of interferon genes(STING)is an adaptor protein that is critical for effective innate antiviral and antitumor immunity.The activity of STING is heavily regulated by protein ubiquitination,which is fine-tune... Stimulator of interferon genes(STING)is an adaptor protein that is critical for effective innate antiviral and antitumor immunity.The activity of STING is heavily regulated by protein ubiquitination,which is fine-tuned by both E3 ubiquitin ligases and deubiquitinases.Here,we report that the deubiquitinase OTUD5 interacts with STING,cleaves its K48-linked polyubiquitin chains,and promotes its stability.Consistently,knockout of OTUD5 resulted in faster turnover of STING and subsequently impaired type I IFN signaling following cytosolic DNA stimulation.More importantly,Lyz2-Cre Otud5^(fl/Y) mice and CD11-Cre Otud5^(fl/Y) mice showed more susceptibility to herpes simplex virus type 1(HSV-1)infection and faster development of melanomas than their corresponding control littermates,indicating that OTUD5 is indispensable for STING-mediated antiviral and antitumor immunity.Our data suggest that OTUD5 is a novel checkpoint in the cGAS-STING cytosolic DNA sensing pathway. 展开更多
关键词 Antiviral innate immunity antitumor immunity STING deubiquitination OTUD5
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Role of deubiquitinating enzymes in DNA double-strand break repair 被引量:6
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作者 Yunhui LI Jian YUAN 《Journal of Zhejiang University-Science B(Biomedicine & Biotechnology)》 SCIE CAS CSCD 2021年第1期63-72,共10页
DNA is the hereditary material in humans and almost all other organisms. It is essential for maintaining accurate transmission of genetic information. In the life cycle, DNA replication, cell division, or genome damag... DNA is the hereditary material in humans and almost all other organisms. It is essential for maintaining accurate transmission of genetic information. In the life cycle, DNA replication, cell division, or genome damage, including that caused by endogenous and exogenous agents, may cause DNA aberrations. Of all forms of DNA damage, DNA double-strand breaks(DSBs) are the most serious. If the repair function is defective, DNA damage may cause gene mutation, genome instability, and cell chromosome loss, which in turn can even lead to tumorigenesis. DNA damage can be repaired through multiple mechanisms. Homologous recombination(HR) and non-homologous end joining(NHEJ) are the two main repair mechanisms for DNA DSBs. Increasing amounts of evidence reveal that protein modifications play an essential role in DNA damage repair.Protein deubiquitination is a vital post-translational modification which removes ubiquitin molecules or polyubiquitinated chains from substrates in order to reverse the ubiquitination reaction. This review discusses the role of deubiquitinating enzymes(DUBs) in repairing DNA DSBs. Exploring the molecular mechanisms of DUB regulation in DSB repair will provide new insights to combat human diseases and develop novel therapeutic approaches. 展开更多
关键词 deubiquitinating enzymes(DUBs) DNA double-strand breaks(DSBs) DNA repair Non-homologous end joining(NHEJ) Homologous recombination(HR)
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USP11 regulates p53 stability by deubiquitinating p53 被引量:2
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作者 Jia-ying KE Cong-jie DAI +5 位作者 Wen-lin WU Jin-hua GAO Ai-juan XIA Guang-ping LIU Kao-sheng LV Chun-lin WU 《Journal of Zhejiang University-Science B(Biomedicine & Biotechnology)》 SCIE CAS CSCD 2014年第12期1032-1038,共7页
The p53 tumor suppressor protein coordinates the cellular responses to a broad range of cellular stresses, leading to DNA repair, cell cycle arrest or apoptosis. The stability of p53 is essential for its tumor suppres... The p53 tumor suppressor protein coordinates the cellular responses to a broad range of cellular stresses, leading to DNA repair, cell cycle arrest or apoptosis. The stability of p53 is essential for its tumor suppressor function, which is tightly controlled by ubiquitin-dependent degradation primarily through its negative regulator mudne double minute 2 (Mdm2). To better understand the regulation of p53, we tested the interaction between p53 and USP11 using co-immunoprecipitation. The results show that USP11, an ubiquitin-specific protease, forms specific complexes with p53 and stabilizes p53 by deubiquitinating it. Moreover, down-regulation of USP11 dramatically attenuated p53 in- duction in response to DNA damage stress. These findings reveal that USP11 is a novel regulator of p53, which is required for p53 activation in response to DNA damage. 展开更多
关键词 P53 USP11 deubiquitinATION STABILITY
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Deubiquitination in prostate cancer progression:role of USP22 被引量:2
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作者 Nivedita Nag Samikshan Dutta 《Journal of Cancer Metastasis and Treatment》 CAS 2020年第1期155-167,共13页
Prostate cancer(PCa)is the leading cause of cancer death in men.With more therapeutic modalities available,the overall survival in PCa has increased significantly in recent years.Patients with relapses after advanced ... Prostate cancer(PCa)is the leading cause of cancer death in men.With more therapeutic modalities available,the overall survival in PCa has increased significantly in recent years.Patients with relapses after advanced secondgeneration anti-androgen therapy however,often show poor disease prognosis.This group of patients often die from cancer-related complicacies.Multiple approaches have been taken to understand disease recurrence and to correlate the gene expression profile.In one such study,an 11-gene signature was identified to be associated with PCa recurrence and poor survival.Amongst them,a specific deubiquitinase called ubiquitin-specific peptidase 22(USP22)was selectively and progressively overexpressed with PCa progression.Subsequently,it was shown to regulate androgen receptors and Myc,the two most important regulators of PCa progression.Furthermore,USP22 has been shown to be associated with the development of therapy resistant PCa.Inhibiting USP22 was also found to be therapeutically advantageous,especially in clinically challenging and advanced PCa.This review provides an update of USP22 related functions and challenges associated with PCa research and explains why targeting this axis is beneficial for PCa relapse cases. 展开更多
关键词 USP22 prostate cancer SAGA deubiquitin
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Dual roles of the Arabidopsis PEAT complex in histone H2A deubiquitination and H4K5 acetylation 被引量:1
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作者 Si-Yao Zheng Bin-Bin Guan +8 位作者 Dan-Yang Yuan Qiang-Qiang Zhao Weiran Ge Lian-Mei Tan Shan-Shan Chen Lin Li She Chen Rui-Ming Xu Xin-Jian He 《Molecular Plant》 SCIE CSCD 2023年第11期1847-1865,共19页
Histone H2A monoubiquitination is associated with transcriptional repression and needs to be removed by deubiquitinases to facilitate gene transcription in eukaryotes.However,the deubiquitinase responsible for genome-... Histone H2A monoubiquitination is associated with transcriptional repression and needs to be removed by deubiquitinases to facilitate gene transcription in eukaryotes.However,the deubiquitinase responsible for genome-wide H2A deubiquitination in plants has yet to be identified.In this study,we found that the previously identified PWWP-EPCR-ARID-TRB(PEAT)complex components interact with both the ubiquitin-specific protease UBP5 and the redundant histone acetyltransferases HAM1 and HAM2(HAM1/2)to form a larger version of PEAT complex in Arabidopsis thaliana.UBP5 functions as an H2A deubiquitinase in a nucleosome substrate-dependent manner in vitro and mediates H2A deubiquitination at the whole-genome level in vivo.HAM1/2 are shared subunits of the PEAT complex and the conserved NuA4 histone acetyltransferase com-plex,and are responsible for histone H4K5 acetylation.Within the PEAT complex,the PWWP components(PWWP1,PWWP2,and PWWP3)directly interact with UBP5 and are necessary for UBP5-mediated H2A deu-biquitination,while the EPCR components(EPCR1 and EPCR2)directly interact with HAM1/2 and are required for HAM1/2-mediated H4K5acetylation.Collectively,our study not onlyidentifies dual roles of thePEAT com-plex in H2A deubiquitination and H4K5 acetylation but also illustrates how these processes collaborate at the whole-genome level to regulate the transcription and development in plants. 展开更多
关键词 HISTONE H2A deubiquitination H4K5 acetylation UBP5 HAM1 NuA4 PEAT
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Deubiquitination of BES1 by UBP12/UBP13 promotes brassinosteroid signaling and plant growth 被引量:1
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作者 Su-Hyun Park Jin Seo Jeong +2 位作者 Yu Zhou Nur Fatimah Binte Mustafa Nam-Hai Chua 《Plant Communications》 SCIE 2022年第5期171-185,共15页
As a key transcription factor in the brassinosteroid (BR) signaling pathway, the activity and expression ofBES1 (BRI1-EMS-SUPPRESSOR 1) are stringently regulated. BES1 degradation is mediated by ubiquitinrelated 26S p... As a key transcription factor in the brassinosteroid (BR) signaling pathway, the activity and expression ofBES1 (BRI1-EMS-SUPPRESSOR 1) are stringently regulated. BES1 degradation is mediated by ubiquitinrelated 26S proteasomal and autophagy pathways, which attenuate and terminate BR signaling;however,the opposing deubiquitinases (DUBs) are still unknown. Here, we showed that the ubp12-2w/13-3 doublemutant phenocopies the BR-deficient dwarf mutant, suggesting that the two DUBs UBP12/UBP13 antagonize ubiquitin-mediated degradation to stabilize BES1. These two DUBs can trim tetraubiquitin with K46 and K63 linkages in vitro. UBP12/BES1 and UBP13/BES1 complexes are localized in bothcytosol and nuclei. UBP12/13 can deubiquitinate polyubiquitinated BES1 in vitro and in planta, andUBP12 interacts with and deubiquitinates both inactive, phosphorylated BES1 and active, dephosphorylated BES1 in vivo. UBP12 overexpression in BES1OE plants significantly enhances cell elongation in hypocotyls and petioles and increases the ratio of leaf length to width compared with BES1OE or UBP12OE plants.Hypocotyl elongation and etiolation result from elevated BES1 levels because BES1 degradation is retardedby UBP12 in darkness or in light with BR. Protein degradation inhibitor experiments show that the majorityof BES1 can be degraded by either the proteasomal or the autophagy pathway, but a minor BES1 fractionremains pathway specific. In conclusion, UBP12/UBP13 deubiquitinate BES1 to stabilize the latter as a positive regulator for BR responses. 展开更多
关键词 UBP12 UBP13 BES1 deubiquitinATION brassinosteroid signaling
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Emerging role of ubiquitination/deubiquitination modification of PD-1/PD-L1 in cancer immunotherapy
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作者 Peng Ding Zhiqiang Ma +8 位作者 Yizeng Fan Yingtong Feng Changjian Shao Minghong Pan Yimeng Zhang Di Huang Jing Han Yi Hu Xiaolong Yan 《Genes & Diseases》 SCIE CSCD 2023年第3期848-863,共16页
As members of the immune checkpoint family, PD-1 and its ligand PD-L1 play critical roles in maintaining the balance between autoimmunity and tolerance. The interaction of PD-1/PD-L1 is also involved in tumor evasion ... As members of the immune checkpoint family, PD-1 and its ligand PD-L1 play critical roles in maintaining the balance between autoimmunity and tolerance. The interaction of PD-1/PD-L1 is also involved in tumor evasion inside the tumor microenvironment, caused by reduced T cell activation, proliferation, cytotoxic secretion, and survival. Previous research has shown that the expression level of PD-1/PD-L1 may be regulated by ubiquitin-mediated proteasome degradation, which is an important mode of post-translational modification (PTM). PD-1/PD-L1 ubiquitin modification research in tumor immunotherapy is the subject of the present review, which aims to assess the most recent developments in this area. We offer a short explanation of PD-1/PD-L1 as well as some basic background information on the UPS system and discuss many routes that target E3s and DUBs, respectively, in the regulation of PD-1/PD-L1 in tumor immunotherapy. In addition, we offer numerous innovative prospective research areas for the future, as well as novel immunotherapy concepts and ideas. Taken together, the information compiled herein should serve as a comprehensive repository of information about tumor immunotherapy that is currently available, and it should be useful in the design of future studies, as well as the development of potential targets and strategies for future tumor immunotherapy. 展开更多
关键词 Cancer deubiquitinATION IMMUNOTHERAPY PD-1 PD-L1 UBIQUITINATION
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Hexyl-pentynoic acid serves as a novel radiosensitizer for breast cancer by inhibiting UCHL3-dependent Rad51 deubiquitination
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作者 Zuchao Cai David Lim +8 位作者 Beidi Jia Guochao Liu Wenwen Ding Zhendong Wang Zhujun Tian Junxuan Peng Fengmei Zhang Chao Dong Zhihui Feng 《Radiation Medicine and Protection》 CSCD 2023年第4期204-213,共10页
Objective:To investigate the effects and underlying mechanism of 2-hexyl-4-pentynoic acid(HPTA),a derivative of valproic acid(VPA),on radiotherapy in breast cancer.Methods:MCF7 cells and 7,12-dimethylbenz-[α]-anthrac... Objective:To investigate the effects and underlying mechanism of 2-hexyl-4-pentynoic acid(HPTA),a derivative of valproic acid(VPA),on radiotherapy in breast cancer.Methods:MCF7 cells and 7,12-dimethylbenz-[α]-anthracene(DMBA)-induced transformed human normal breast cells(MCF10A–DMBA cells)were irradiated with 8 Gy X-rays.For both cells there were four groups:control,valproic acid(VPA)/HPTA,IR,and VPA/HPTA+IR groups.MTT and clonogenic survival assays were performed to assess cell proliferation,and comet assay was performed to evaluate DNA damage.Protein expression ofγH2AX,53BP1,Rad51,and BRCA1 was examined via immunofluorescence and immunoblotting.Cycloheximide chase and ubiquitination experiments were conducted to determine Rad51 ubiquitination.In vivo experiments involved a rat model of DMBA-induced breast cancer,with four fractionated doses of 2 Gy.Tumor tissue pathological changes andγH2AX,Rad51,and UCHL3 expression levels were measured by hematoxylin-eosin staining,immunohistochemistry,and immunoblotting.Results:Compared with the IR group,15μmol/L HPTA reduced the cell proliferation ability of irradiated MCF7 cells(t=2.16,P<0.05).The VPA/HPTA+IR group exhibited significantly increased DNA double-strand breaks relative to those in the IR group(VPA+IR vs.IR,t=13.37,P<0.05;HPTA+IR vs.IR,t=8.48,P<0.05).Immunofluorescence and immunoblotting experiments demonstrated that the VPA/HPTA+IR group displayed signifi-cantly increased cell foci formation,γH2AX and 53BP1 protein expression levels compared to the IR group[(γH2AX:VPA+IR vs.IR,t=8.88,P<0.05;HPTA+IR vs.IR,t=8.90,P<0.05),(53BP1,VPA+IR vs.IR,t=5.73,P<0.05;HPTA+IR vs.IR,t=6.40,P<0.05)].Further,Rad51 expression was downregulated(VPA+IR vs.IR,t=3.12,P<0.05;HPTA+IR vs.IR,t=2.70,P<0.05),and Rad51 inhibition effectively counteracted HPTA-induced radiosensitization.Ubiquitination detection further verified that HPTA inhibits Rad51 expression via UCHL3-dependent Rad51 deubiquitination.In vivo study results showed that 20 mg/kg HPTA significantly enhanced the radiosensitivity of breast tumors in rats by inhibiting Rad51 expression.Conclusions:HPTA is a highly effective radiosensitizer that enhances the radiotherapeutic efficacy of breast cancer treatment through UCHL3-dependent deubiquitination of Rad51. 展开更多
关键词 2-hexyl-4-pentynoic acid RADIOSENSITIZATION UCHL3 RAD51 Homologous recombination deubiquitinATION
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泛素-蛋白酶体系统在寄生原虫生长发育中的调控作用及潜在药物靶点分析 被引量:1
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作者 孙宏宇 于丹 +2 位作者 孔繁利 冯宪敏 刘迪 《吉林医药学院学报》 2024年第4期286-290,295,共6页
蛋白质降解是细胞维持正常生命活动的重要途径之一,其中泛素-蛋白酶体系统发挥关键作用。泛素-蛋白酶体系统参与调控细胞分化、细胞凋亡、DNA复制、蛋白质质量控制等生命活动。研究表明,对该系统中的功能蛋白进行干预,可直接影响寄生原... 蛋白质降解是细胞维持正常生命活动的重要途径之一,其中泛素-蛋白酶体系统发挥关键作用。泛素-蛋白酶体系统参与调控细胞分化、细胞凋亡、DNA复制、蛋白质质量控制等生命活动。研究表明,对该系统中的功能蛋白进行干预,可直接影响寄生原虫的生长发育。本文主要探讨近年关于泛素-蛋白酶体系统在寄生原虫生长分化过程中发挥的关键作用,揭示其作用靶点,为开发新型抗原虫药物提供思路。 展开更多
关键词 泛素-蛋白酶体系统 泛素化 去泛素化酶 蛋白酶体 药物靶点
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USP19 Stabilizes TAK1 to Regulate High Glucose/Free Fatty Acid-induced Dysfunction in HK-2 Cells
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作者 Xiao-hui YAN Yin-na ZHU Yan-ting ZHU 《Current Medical Science》 SCIE CAS 2024年第4期707-717,共11页
Objective Obesity-induced kidney injury contributes to the development of diabetic nephropathy(DN).Here,we identified the functions of ubiquitin-specific peptidase 19(USP19)in HK-2 cells exposed to a combination of hi... Objective Obesity-induced kidney injury contributes to the development of diabetic nephropathy(DN).Here,we identified the functions of ubiquitin-specific peptidase 19(USP19)in HK-2 cells exposed to a combination of high glucose(HG)and free fatty acid(FFA)and determined its association with TGF-beta-activated kinase 1(TAK1).Methods HK-2 cells were exposed to a combination of HG and FFA.USP19 mRNA expression was detected by quantitative RT-PCR(qRT-PCR),and protein analysis was performed by immunoblotting(IB).Cell growth was assessed by Cell Counting Kit-8(CCK-8)viability and 5-ethynyl-2′-deoxyuridine(EdU)proliferation assays.Cell cycle distribution and apoptosis were detected by flow cytometry.The USP19/TAK1 interaction and ubiquitinated TAK1 levels were assayed by coimmunoprecipitation(Co-IP)assays and IB.Results In HG+FFA-challenged HK-2 cells,USP19 was highly expressed.USP19 knockdown attenuated HG+FFA-triggered growth inhibition and apoptosis promotion in HK-2 cells.Moreover,USP19 knockdown alleviated HG+FFA-mediated PTEN-induced putative kinase 1(PINK1)/Parkin pathway inactivation and increased mitochondrial reactive oxygen species(ROS)generation in HK-2 cells.Mechanistically,USP19 stabilized the TAK1 protein through deubiquitination.Importantly,increased TAK1 expression reversed the USP19 knockdown-mediated phenotypic changes and PINK1/Parkin pathway activation in HG+FFA-challenged HK-2 cells.Conclusion The findings revealed that USP19 plays a crucial role in promoting HK-2 cell dysfunction induced by combined stimulation with HG and FFAs by stabilizing TAK1,providing a potential therapeutic strategy for combating DN. 展开更多
关键词 HK-2 cells high glucose free fatty acid DYSFUNCTION USP19 deubiquitinATION
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泛素化在调控铁死亡中的作用
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作者 曹灿 陶永光 石颖 《生物化学与生物物理进展》 SCIE CAS CSCD 北大核心 2024年第6期1269-1283,共15页
铁死亡是一种由脂质过氧化驱动的铁依赖性的新的细胞死亡方式,越来越多的证据表明,铁死亡与各种病理状态有关,如神经退行性疾病、糖尿病肾病、癌症等,脂质过氧化驱动的铁死亡可能促进或抑制这些疾病的发生发展,细胞中抗氧化系统通过抑... 铁死亡是一种由脂质过氧化驱动的铁依赖性的新的细胞死亡方式,越来越多的证据表明,铁死亡与各种病理状态有关,如神经退行性疾病、糖尿病肾病、癌症等,脂质过氧化驱动的铁死亡可能促进或抑制这些疾病的发生发展,细胞中抗氧化系统通过抑制脂质过氧化在抵抗铁死亡过程中发挥着重要作用。铁死亡的关键通路有以SLC7A11-GPX4为关键分子的氨基酸代谢通路、以铁蛋白或转铁蛋白为主的铁代谢通路,以及脂质代谢通路。铁死亡的发生受到细胞内蛋白质的调节,这些蛋白质会发生各种翻译后修饰,包括泛素化修饰。泛素-蛋白酶体系统(ubiquitin-proteasome system,UPS)是细胞内主要降解系统之一,通过酶促级联反应催化泛素分子标记待降解蛋白,随后由蛋白酶体识别并降解目标蛋白质。UPS根据其降解底物的不同在调节铁死亡的反应中发挥双重作用。UPS通过促进铁死亡关键分子(如SLC7A11、GPX4、GSH)以及抗氧化系统成分(如NRF2)的泛素化降解从而促进铁死亡,也可以通过促进脂质代谢通路中相关分子(如ACSL4、ALOX15)的泛素化降解从而抑制铁死亡。本综述介绍泛素化修饰在调控铁死亡进程中作用的最新研究进展,总结了已发表的关于E3泛素连接酶和去泛素酶调控铁死亡的研究,归纳了泛素连接酶、去泛素酶调控铁死亡的作用靶点,有助于确定人类疾病中新的预后指标,为这些疾病提供潜在的治疗策略。 展开更多
关键词 铁死亡 泛素化 去泛素化 脂质过氧化
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去泛素化酶调控骨改建相关信号通路的研究进展
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作者 杨琳 段霏 +3 位作者 李朋礼 陈琦 杨燕美 顾斌 《解放军医学院学报》 CAS 2024年第8期898-903,共6页
去泛素化酶通过去除蛋白连接的泛素链,在维持细胞蛋白质的功能和稳定性中发挥关键作用。近年来不断有研究发现去泛素化酶参与调节生长发育进程中的骨改建过程。骨改建达到功能平衡需要多种信号通路参与其中,如成骨相关的Wnt/β-catenin... 去泛素化酶通过去除蛋白连接的泛素链,在维持细胞蛋白质的功能和稳定性中发挥关键作用。近年来不断有研究发现去泛素化酶参与调节生长发育进程中的骨改建过程。骨改建达到功能平衡需要多种信号通路参与其中,如成骨相关的Wnt/β-catenin、BMP信号通路,骨吸收相关的NF-κB、RANKL/RANK信号通路等。本文简要介绍了泛素-去泛素化过程,并且就去泛素化酶通过调控成骨、破骨信号通路蛋白的功能和稳定性参与骨改建进行综述。 展开更多
关键词 泛素化 去泛素化酶 骨形成 骨吸收 信号通路
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MYSM1对大鼠颌骨骨髓间充质干细胞增殖和成骨分化能力的影响
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作者 杨琳 杨燕美 +3 位作者 李朋礼 陈琦 胡雅雯 顾斌 《解放军医学院学报》 CAS 2024年第6期659-665,F0003,共8页
背景去泛素化酶能够调控骨骼生长发育,MYSM1基因缺失会造成全身骨骼疏松,当前并无MYSM1对颌骨发育影响的研究。目的探讨MYSM1对颌骨来源的骨髓间充质干细胞成骨分化能力的影响。方法分离10只8周Wistar大鼠下颌骨,利用组织消化法分离培... 背景去泛素化酶能够调控骨骼生长发育,MYSM1基因缺失会造成全身骨骼疏松,当前并无MYSM1对颌骨发育影响的研究。目的探讨MYSM1对颌骨来源的骨髓间充质干细胞成骨分化能力的影响。方法分离10只8周Wistar大鼠下颌骨,利用组织消化法分离培养颌骨骨髓间充质干细胞(jaw bone marrow mesenchymal stem cells,JBMMSCs)。取生长良好的第3~5代JBMMSCs进行成骨诱导,利用qPCR、Western blot技术检测成骨标志物OCN、Runx2、ALP及去泛素化酶MYSM1的变化。分别利用空转染慢病毒和MYSM1敲低的慢病毒转染JBMMSCs,设置对照组和敲低组细胞,qPCR检测敲低效率。CCK-8、细胞克隆形成实验检测其敲低MYSM1对细胞的增殖能力影响,细胞划痕实验检测细胞迁移能力。空转染慢病毒和敲低MYSM1的JBMMSCs成骨诱导7 d后利用qPCR技术、ALP、茜素红染色检测成骨的表达变化。结果JBMMSCs成骨诱导成功后,MYSM1的mRNA和蛋白表达水平升高(P<0.05)。CCK-8显示对照组和敲低组的细胞增殖能力无统计学差异(P>0.05),两组间细胞集落形成实验和细胞迁移能力有统计学差异(P<0.05)。敲低组JBMMSCs在成骨诱导7 d后OCN、Runx2、ALP的mRNA表达水平降低(P<0.05),ALP、茜素红染色浅于对照组。结论敲低MYSM1并未对JBMMSs的增殖和迁移能力造成显著影响,而敲低MYSM1的JBMMSCs成骨分化能力降低。 展开更多
关键词 去泛素化酶 MYSM1 颌骨骨髓间充质干细胞 成骨分化 细胞增殖
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蛋白泛素化修饰在脓毒症中的作用研究进展
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作者 牛泽粟 胡怡 +2 位作者 杨丽婷 陈梦飞 潘东峰 《中国急救复苏与灾害医学杂志》 2024年第5期682-685,692,共5页
脓毒症是指由于感染反应失调引起的多器官功能障碍。泛素化是指泛素分子在多种泛素化相关酶的作用下对靶蛋白进行特异性修饰的过程。近年来,有研究发现泛素化-蛋白酶体系统与脓毒症的病理生理过程存在密切关系。随着泛素化与炎症之间的... 脓毒症是指由于感染反应失调引起的多器官功能障碍。泛素化是指泛素分子在多种泛素化相关酶的作用下对靶蛋白进行特异性修饰的过程。近年来,有研究发现泛素化-蛋白酶体系统与脓毒症的病理生理过程存在密切关系。随着泛素化与炎症之间的病理生理机制的研究逐渐深入,选择泛素化过程作为脓毒症的治疗靶点将成为一个新的研究方向。 展开更多
关键词 脓毒症 泛素化 炎症 去泛素化
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