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

Frontiers of Medicine 2024年第3期18卷 465-483页

作者： Fei Xu Han Chen Changyi Zhou Tongtong Zang Rui Wang Shutong Shen Chaofu Li Yue Yu Zhiqiang Pei Li Shen Juying Qian Junbo Ge Department of Cardiology and Laboratory of Heart Valve Disease West China HospitalSichuan UniversityChengdu610041China Department of Cardiology Zhongshan HospitalFudan UniversityResearch Unit of Cardiovascular Techniques and DevicesChinese Academy of Medical SciencesShanghai200032China Shanghai Institute of Cardiovascular Diseases Shanghai200032China National Clinical Research Center for Interventional Medicine&Shanghai Clinical Research Center for Interventional Medicine(19MC1910300) Shanghai200032China

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 PDGFRβwith its catalytic triad,thereby reducing the K48-linked ubiquitylation of PDGFRβ.Inhibiting OTUB1 in VSMCs could promote PDGFRβdegradation 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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deubiquitinase ubiquitin-specific protease 3 (USP3) inhibits HIV-1 replication via promoting APOBEC3G (A3G) expression in both enzyme activity-dependent and -independent manners

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Chinese Medical Journal 2022年第22期135卷 2706-2717页

作者： Simin Zhao Baisong Zheng Liuli Wang Wenzhe Cui Chunlai Jiang Zhuo Li Wenying Gao Wenyan Zhang Center for Pathogen Biology and Infectious Diseases Institute of Virology and AIDS ResearchKey Laboratory of Organ Regeneration and Transplantation of The Ministry of EducationThe First Hospital of Jilin UniversityChangchunJilin 130021China College of Life Science of Jilin University ChangchunJilin 130012China Department of Regenerative Medicine School of Pharmaceutical SciencesJilin UniversityChangchunJilin 130012China Jilin Provincial Key Laboratory on Molecular and Chemical Genetics The Second Hospital of Jilin UniversityChangchunJilin 130041China Department of Endocrinology and Metabolism The First Hospital of Jilin UniversityChangchunJilin 130021China

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.

关键词： APOBEC3G Ubiquitin-specific protease 3 Deubiquitination Human immunodeficiency virus-1 Vif Human immunodeficiency virus deubiquitinase

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Blockade of deubiquitinase YOD1 degrades oncogenic PML/RARα and eradicates acute promyelocytic leukemia cells

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1856-1870页

作者： Xuejing Shao Yingqian Chen Wei Wang Wenxin Du Xingya Zhang Minyi Cai Shaowei Bing Ji Cao Xiaojun Xu Bo Yang Qiaojun He Meidan Ying Institute of Pharmacology and Toxicology Zhejiang Province Key Laboratory of Anti-Cancer Drug ResearchCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China Children’s Hospital Zhejiang University School of MedicineNational Clinical Research Center for Child HealthHangzhou 310052China Cancer Center Zhejiang UniversityHangzhou 310058China Innovation Institute for Artificial Intelligence in Medicine Zhejiang UniversityHangzhou 310058China

In most acute promyelocytic leukemia(APL)cells,promyelocytic leukemia(PML)fuses to retinoic acid receptor α (RARα)due to chromosomal translocation,thus generating PML/RARαoncoprotein,which is a relatively stable oncoprotein for degradation in APL.Elucidating the mechanism regulating the stability of PML/RARαmay help to degrade PML/RARαand eradicate APL cells.Here,we describe a deubiquitinase(DUB)-involved regulatory mechanism for the maintenance of PML/RARαstability and develop a novel pharmacological approach to degrading PML/RARαby inhibiting DUB.We utilized a DUB siRNA library to identify the ovarian tumor protease(OTU)family member deubiquitinase YOD1 as a critical DUB of PML/RARα.Suppression of YOD1 promoted the degradation of PML/RARα,thus inhibiting APL cells and prolonging the survival time of APL cell-bearing mice.Subsequent phenotypic screening of small molecules allowed us to identify ubiquitin isopeptidase inhibitor I(G5)as the first YOD1 pharmacological inhibitor.As expected,G5 notably degraded PML/RARαprotein and eradicated APL,particularly drug-resistant APL cells.Importantly,G5 also showed a strong killing effect on primary patient-derived APL blasts.Overall,our study not only reveals the DUB-involved regulatory mechanism on PML/RARαstability and validates YOD1 as a potential therapeutic target for APL,but also identifies G5 as a YOD1 inhibitor and a promising candidate for APL,particularly drug-resistant APL treatment.

关键词： Acute promyelocytic leukemia PML/RARa deubiquitinase YOD1 Degradation Drug resistance Inhibitor Therapy

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deubiquitinase JOSD2 stabilizes YAP/TAZ to promote cholangiocarcinoma progression

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Acta Pharmaceutica Sinica B 2021年第12期11卷 4008-4019页

作者： Meijia Qian Fangjie Yan Weihua Wang Jiamin Du Tao Yuan Ruilin Wu Chenxi Zhao Jiao Wang Jiabin Lu Bo Zhang Nengming Lin Xin Dong Xiaoyang Dai Xiaowu Dong Bo Yang Hong Zhu Qiaojun He Zhejiang Province Key Laboratory of Anti-Cancer Drug Research College of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China Innovation Institute for Artificial Intelligence in Medicine Zhejiang UniversityHangzhou 310058China Department of Clinical Pharmacology Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang ProvinceAffiliated Hangzhou First People’s HospitalCancer CenterZhejiang University School of MedicineHangzhou 310006China Second Affiliated Hospital School of MedicineZhejiang UniversityHangzhou 310009China Cancer Center of Zhejiang University Hangzhou 310058China

Cholangiocarcinoma(CCA)has emerged as an intractable cancer with scanty therapeutic regimens.The aberrant activation of Yes-associated protein(YAP)and transcriptional co-activator with PDZ-binding motif(TAZ)are reported to be common in CCA patients.However,the underpinning mechanism remains poorly understood.deubiquitinase(DUB)is regarded as a main orchestrator in maintaining protein homeostasis.Here,we identified Josephin domain-containing protein 2(JOSD2)as an essential DUB of YAP/TAZ that sustained the protein level through cleavage of polyubiquitin chains in a deubiquitinase activity-dependent manner.The depletion of JOSD2 promoted YAP/TAZ proteasomal degradation and significantly impeded CCA proliferation in vitro and in vivo.Further analysis has highlighted the positive correlation between JOSD2 and YAP abundance in CCA patient samples.Collectively,this study uncovers the regulatory effects of JOSD2 on YAP/TAZ protein stabilities and profiles its contribution in CCA malignant progression,which may provide a potential intervention target for YAP/TAZ-related CCA patients.

关键词： Cholangiocarcinoma deubiquitinase JOSD2 YAP/TAZ

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Regulation of antiviral innate immunity by deubiquitinase CYLD

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Cellular & Molecular Immunology 2011年第6期8卷 502-504页

作者： Minying Zhang Andrew J Lee Xuefeng Wu Shao-Cong Sun Department of Immunology The University of Texas MD Anderson Cancer CenterHoustonTXUSA Department of Melanoma Medical Oncology The University of Texas MD Anderson Cancer CenterHoustonTXUSA Laboratory of Gene Regulation and Signal Transduction Department of PharmacologySchool of MedicineUniversity of California at San DiegoLa JollaCAUSA

An antiviral innate immune response involves induction of type I interferons(IFNs)and their subsequent autocrine and paracrine actions,but the underlying regulatory mechanisms are incompletely understood.Here we report that CYLD,a deubiquitinase that specifically digests lysine 63-linked ubiquitin chains,is required for antiviral host defense.Loss of CYLD renders mice considerably more susceptible to infection by vesicular stomatitis virus(VSV).Consistently,CYLD-deficient dendritic cells are more sensitive to VSV infection.This functional defect was not due to lack of type I IFN production but rather because of attenuated IFN receptor signaling.In the absence of CYLD,IFN-b is ineffective in the induction of antiviral genes and protection of cells from viral infection.These findings establish CYLD as a novel regulator of antiviral innate immunity and suggest a role for CYLD in regulating IFN receptor signaling.

关键词： antiviral innate immunity CYLD deubiquitinase interferon VSV

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Semi-synthesis of Ubiquitin-propargylamide for identifying deubiquitinase targeting inhibitors

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Chinese Chemical Letters 2019年第3期30卷 743-746页

作者： Xiaodan Tan Jingsi Bai Shan Ding Yujing Ren Danning Hong Ziqing Mei Yi-Ming Li School of Biological and Medical Engineering Hefei University of Technology Tsinghua-Peking Center for Life Sciences Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical BiologyDepartment of Chemistry Tsinghua University Biotechnology Research Institute Chinese Academy of Agricultural Sciences School of Biological Science Beijing Institute of Technology

Ubiquitin-propargylamide(Ub-PA) is one of the most widely used activity-based probe to measure the activity of deubiquitinases(DUBs) and help validate DUBs targeting inhibitors. However, current synthetic route of Ub-PA is cumbersome. In this work, we report a novel semi-synthetic strategy to prepare Ub-PA in large-scale. Biochemical assays prove that semi-synthetic Ub-PA is an effective probe in identifying DUBs targeting inhibitors.

关键词： deubiquitinase Activity-based probe Ubiquitin-propargylamide Protein semi-synthesis Inhibitor identification

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The USP7 protein interaction network and its roles in tumorigenesis

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Genes & Diseases 2022年第1期9卷 41-50页

作者： Ahood Al-Eidan Yihua Wang Paul Skipp Rob M.Ewing School of Biological Sciences B85 Life SciencesUniversity of SouthamptonSouthamptonSO171BJUK Department of Biology College of SciencesImam Abdulrahman Bin Faisal UniversityP.O.Box 1982DammamSaudi Arabia

Ubiquitin-specific protease(USP7),also known as Herpesvirus-associated ubiquitin-specific protease(HAUSP),is a deubiquitinase.There has been significant recent attention on USP7 following the discovery that USP7 is a key regulator of the p53-MDM2 pathway.The USP7 protein is 130 kDa in size and has multiple domains which bind to a diverse set of proteins.These interactions mediate key developmental and homeostatic processes including the cell cycle,immune response,and modulation of transcription factor and epigenetic regulator activity and localization.USP7 also promotes carcinogenesis through aberrant activation of the Wnt signalling pathway and stabilization of HIF-1α.These findings have shown that USP7 may induce tumour progression and be a therapeutic target.Together with interest in developing USP7 as a target,several studies have defined new protein interactions and the regulatory networks within which USP7 functions.In this review,we focus on the protein interactions of USP7 that are most important for its cancer-associated roles.

关键词： Cancer deubiquitinase Protein network Protein-protein interaction Proteomics USP7

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deubiquitinases as pivotal regulators of T cell functions

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Frontiers of Medicine 2018年第4期12卷 451-462页

作者： Xiao-Dong Yang Shao-Cong Sun Shanghai Institute of Immunology Shanghai Jiao Tong University School of Medicine Shanghai 200025 China Department of Immunology The University of Texas MD Anderson Cancer Center 7455 Fannin Street Box 902 Houston TX 77030 USA The University of Texas Graduate School of Biomedical Sciences at Houston Houston TX 77030 USA

T cells efficiently respond to foreign antigens to mediate immune responses against infections but are tolerant to self-tissues. Defect in T cell activation is associated with severe immune deficiencies, whereas aberrant T cell activation contributes to the pathogenesis of diverse autoimmune and inflammatory diseases. An emerging mechanism that regulates T cell activation and tolerance is ubiquitination, a reversible process of protein modification that is counter-regulated by ubiquitinating enzymes and deubiquitinases （DUBs）. DUBs are isopeptidases that cleave polyubiquitin chains and remove ubiquitin from target proteins, thereby controlling the magnitude and duration of ubiquitin signaling. It is now well recognized that DUBs are crucial regulators of T cell responses and serve as potential therapeutic targets for manipulating immune responses in the treatment of immunological disorders and cancer. This review will discuss the recent progresses regarding the functions of DUBs in T cells.

关键词： deubiquitinase ubiquitination T cell activation T cell differentiation T cell tolerance

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How are MCPIP1 and cytokines mutually regulated in cancer-related immunity?

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Protein & Cell 2020年第12期11卷 881-893页

作者： Ruyi Xu Yi Li Yang Liu Jianwei Qu Wen Cao Enfan Zhang Jingsong He Zhen Cai Bone Marrow Transplantation Center The First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou 310006China Institution of Hematology Zhejiang UniversityHangzhou 310006China

Cytokines are secreted by various cell types and act as critical mediators in many physiological processes,including immune response and tumor progression.Cytokines production is precisely and timely regulated by multiple mechanisms at different levels,ranging from transcriptional to post-transcriptional and posttranslational processes.Monocyte chemoattractant protein-1 induced protein 1(MCPIP1),a potent immunosuppressive protein,was first described as a transcription factor in monocytes treated with monocyte chemoattractant protein-1(MCP-1)and subsequently found to possess intrinsic RNase and deubiquitinase activities.MCPIP1 tightly regulates cytokines expression via various functions.Furthermore,cytokines such as interleukin 1 beta(IL-1B)and MCP-1 and inflammatory cytokines inducer lipopolysaccharide(LPS)strongly induce MCPIP1 expression.Mutually regulated MCPIP1 and cytokines form a complicated network in the tumor environment.In this review,we summarize how MCPIP1 and cytokines reciprocally interact and elucidate the effect of the network formed by these components in cancer-related immunity with aim of exploring potential clinical benefits of their mutual regulation.

关键词： MCPIP1 cytokines cancer-related immunity RNase deubiquitinase

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Regulation of inflammasomes by ubiquitination

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Cellular & Molecular Immunology 2016年第6期13卷 722-728页

作者： Joseph S Bednash Rama K Mallampalli Division of Pulmonary Allergy and Critical Care Medicine Department of Medicine Acute Lung injury Center of Excellence University of Pittsburgh Pittsburgh PA 15213 USA Department of Cell Biology and Physiology and Bioengineering University of Pittsburgh Pittsburgh PA 15213 USA Medical Specialty Service Line Veterans Affairs Pittsburgh Healthcare System Pittsburgh PA 15240 USA

Inflammasomes are multi-protein complexes that regulate the innate immune response by facilitating the release of inflammatory cytokines in response to pathogen exposure or cellular damage. Pro-inflammatory inflammasome signaling is vital to host defense and helps initiate the process of tissue repair following an insult to the host, but can be injurious, when excessive or chronic. As such, inflammasome activity is tightly regulated. Here we discuss one critical mechanism of inflammasome regulation, ubiquitination, that functions as a universal modulator of protein stability and trafficking. Recent studies have provided important insights into the regulation of inflammasome activation by protein ubiquitination. We review the molecular regulation of inflammasome function, specifically, as it relates to ubiquitination, and discuss the implications for the development of theraoeutics to soecificallv target aberrant inflammasome signaling.

关键词： deubiquitinase E3 ligase inflammasome innate immunity ubiqutin

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