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药学学报:英文版 2023年第7期13卷 2955-2962页

作者： Yi-Zheng Fang Li Jiang Qiaojun He Ji Cao Bo Yang Institute of Pharmacology and Toxicology Zhejiang Province Key Laboratory of Anti-Cancer Drug ResearchCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China The Innovation Institute for Artificial Intelligence in Medicine Zhejiang UniversityHangzhou 310018China Cancer Center of Zhejiang University Hangzhou 310058China Center for Drug Safety Evaluation and Research of Zhejiang University Hangzhou 310058China

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.

关键词： Deubiquitinating enzyme(DUB) deubiquitination Substrate specificity Complex Scaffold Protein partner

Emerging role of ubiquitination/deubiquitination modification of PD-1/PD-L1 in cancer immunotherapy

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Genes & Diseases 2023年第3期10卷 848-863页

作者： Peng Ding Zhiqiang Ma Yizeng Fan Yingtong Feng Changjian Shao Minghong Pan Yimeng Zhang Di Huang Jing Han Yi Hu Xiaolong Yan Department of Thoracic Surgery Tangdu HospitalThe Air Force Military Medical UniversityXi'anShaanxi 710038China Department of Medical Oncology Senior Department of OncologyThe Fifth Medical Center of PLA General HospitalBeijing 100853China Department of Urology The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxi 710061China Department of Ophthalmology Tangdu HospitalThe Air Force Medical UniversityXi'anShaanxi 710038China

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.

关键词： Cancer deubiquitination Immunotherapy PD-1 PD-L1 Ubiquitination

Hexyl-pentynoic acid serves as a novel radiosensitizer for breast cancer by inhibiting UCHL3-dependent Rad51 deubiquitination

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Radiation Medicine and Protection 2023年第4期4卷 204-213页

作者： Zuchao Cai David Lim Beidi Jia Guochao Liu Wenwen Ding Zhendong Wang Zhujun Tian Junxuan Peng Fengmei Zhang Chao Dong Zhihui Feng Department of Occupational Health and Occupational Medicine School of Public HealthCheeloo College of MedicineShandong UniversityJinan 250012China Stomatology Hospital School of StomatologyZhejiang University School of MedicineZhejiang Provincial Clinical Research Center for Oral DiseasesKey Laboratory of Oral Biomedical Research of Zhejiang ProvinceCancer Center of Zhejiang UniversityHangzhou 310000China Translational Health Research Institute School of Health SciencesWestern Sydney UniversityCampbelltownNew South WalesAustralia College of Medicine and Public Health Flinders UniversityBedford ParkSouth AustraliaAustralia

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,Pdeubiquitination.In vivo study results showed that 20 mg/kg HPTA significantly enhanced the radiosensiti

关键词： 2-hexyl-4-pentynoic acid Radiosensitization UCHL3 Rad51 Homologous recombination deubiquitination

deubiquitination of BES1 by UBP12/UBP13 promotes brassinosteroid signaling and plant growth

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Plant Communications 2022年第5期3卷 171-185页

作者： Su-Hyun Park Jin Seo Jeong Yu Zhou Nur Fatimah Binte Mustafa Nam-Hai Chua Temasek Life Sciences Laboratory National University of Singapore1 Research LinkSingapore 117604Singapore Present address:Wilmar International Limited 28 Biopolis RoadSingapore 138568Singapore

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.

关键词： UBP12 UBP13 BES1 deubiquitination brassinosteroid signaling

The role of ubiquitination and deubiquitination in the regulation of cell junctions

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Protein & Cell 2018年第9期9卷 754-769页

作者： Junting Cai Miranda K. Culley Yutong Zhao Jing Zhao Acute Lung Injury Center of Excellence Division of Pulmonary Asthma and Critical Care Medicine Department of Medicine The University of Pittsburgh Pittsburgh PA 15213 USA Xiangya Hospital of Central South University Changsha 410008 China

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.

关键词： cell-cell junctions protein stability ubiquitination deubiquitination Rho GTPases

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

METTL5 stabilizes c-Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression

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Cancer Communications 2023年第3期43卷 338-364页

作者： Peng Xia Hao Zhang Haofeng Lu Kequan Xu Xiang Jiang Yuke Jiang Xiangdong Gongye Zhang Chen Jie Liu Xi Chen Weijie Ma Zhonglin Zhang Yufeng Yuan Department of Hepatobiliary&Pancreatic Surgery Zhongnan Hospital ofWuhan UniversityWuhanHubeiP.R.China Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary&Pancreatic Diseases of Hubei Province WuhanHubeiP.R.China Department of Hepatobiliary Surgery The First Affiliated Hospital of Yangtze UniversityJingzhouHubeiP.R.China Department of Clinical and Translational Research Center Shenzhen People’s Hospital(The Second Clinical Medical CollegeJinan UniversityThe First Affiliated HospitalSouthern University of Science and Technology)ShenzhenGuangdongP.R.China

Background:Hepatocellular carcinoma(HCC)is one of the most prevalent cancers in the world,with a high likelihood of metastasis and a dismal prognosis.The reprogramming of glucosemetabolism is critical in the development ofHCC.TheWarburg effect has recently been confirmed to occur in a variety of cancers,including HCC.However,little is known about the molecular biological mechanisms underlying the Warburg effect in HCC cells.In this study,we sought to better understand how methyltransferase 5,N6-adenosine(METTL5)controls the development of HCC and theWarburg effect.Methods:In the current study,quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of METTL5 in HCC tissues and cell lines.Several different cell models and animal models were established to determine the role of METTL5 in glucose metabolism reprogramming and the underlying molecularmechanism of HCC.Glutathione-S-transferase pulldown,coimmunoprecipitation,RNA sequencing,non-targeted metabolomics,polysome profiling,and luciferase reporter assays were performed to investigate the molecular mechanisms of METTL5 in HCC cells.Results:We discovered that METTL5 drove glucose metabolic reprogramming to promote the proliferation and metastasis of HCC.Mechanistically,upregulation of METTL5 promoted c-Myc stability and thus activated its downstream glycolytic genes lactate dehydrogenase A(LDHA),enolase 1(ENO1),triosephosphate isomerase 1(TPI1),solute carrier family 2 member 1(SLC2A1),and pyruvate kinase M2(PKM2).The c-Box and ubiquitin binding domain(UBA)regions of ubiquitin specific peptidase 5(USP5)binded to c-Myc protein and inhibited K48-linked polyubiquitination of c-Myc.Further study revealed that METTL5 controled the USP5 translation process,which in turn regulated the ubiquitination of c-Myc.Furthermore,we identified cAMP responsive element binding protein 1(CREB1)/P300 as a critical transcriptional regulator ofMETTL5 that promoted the transcription of METTL5 in HCC.In patient-derived tumor xenograft(PDX)m

关键词： METTL5 c-Myc USP5 P300 CREB1 deubiquitination hepatocellular carcinoma glucose metabolism

Mechanism of inhibiting type I interferon induction by hepatitis B virus X protein

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Protein & Cell 2010年第12期1卷 1106-1117页

作者： Junyi Jiang Hong Tang Key laboratory of Infection and Immunity of Chinese Academy of Sciences Institute of BiophysicsBeijing 100101China Graduate School of Chinese Academy of Sciences Beijing 100049China

Hepatitis B virus(HBV)is regarded as a stealth virus,invading and replicating efficiently in human liver undetected by host innate antiviral immunity.Here,we show that type I interferon(IFN)induction but not its downstream signaling is blocked by HBV replication in HepG2.2.15 cells.This effect may be partially due to HBV X protein(HBx),which impairs IFNβpromoter activation by both Sendai virus(SeV)and components implicated in signaling by viral sensors.As a deubiquitinating enzyme(DUB),HBx cleaves Lys63-linked polyubiquitin chains from many proteins except TANK-binding kinase 1(TBK1).It binds and deconjugates retinoic acid-inducible gene I(RIG I)and TNF receptor-associated factor 3(TRAF3),causing their dissociation from the downstream adaptor CARDIF or TBK1 kinase.In addition to RIG I and TRAF3,HBx also interacts with CARDIF,TRIF,NEMO,TBK1,inhibitor of kappa light polypeptide gene enhancer in B-cells,kinase epsilon(IKKi)and interferon regulatory factor 3(IRF3).Our data indicate that multiple points of signaling pathways can be targeted by HBx to negatively regulate production of type I IFN.

关键词： hepatitis B virus(HBV) HBV X protein(HBx) deubiquitination type I interferon

CD36： linking lipids to the NLRP3 inflammasome, atherogenesis and atherothrombosis

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Cellular & Molecular Immunology 2014年第1期11卷 8-10页

作者： Cecile Oury GIGA-Research Human Genetics Unit Laboratoryof Thrombosis and Hemostasis University of LiegeLiege Belgium

Arecent study published in Nature Immunology by Sheedy et al.1 indicates that uptake of modified low-den- sity lipoprotein （LDL） by the scavenger receptor CD36 primes and activates the NLRP3 inflammasome, providing an early pathogenic pathway that links cho- lesterol accumulation to the chronic inflammatory process of atherosclero- sis.1 Atherosclerosis arises from chronic vascular inflammation elicited by lipids.

关键词： STERILE INFLAMMATION ACTIVATION deubiquitination LIGANDS MICE

Biochemical properties of K_(11,48)-branched ubiquitin chains

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Chinese Chemical Letters 2018年第7期29卷 1155-1159页

作者： Lu-Jun Liang Yanyan Si Shan Tang Dongliang Huang Zhipeng A.Wang Changlin Tian Ji-Shen Zheng School of Life Sciences University of Science and Technology of China

As one of the most widely existing post-translational modification models, ubiquitination regulates diverse cellular activities. In eukaryotes, K-branched ubiquitin chains play key roles in cell cycle and protein quality control. However, the structural and biochemical properties of K-branched ubiquitin chains have not been well examined. Here we employed the synthetic linkage-and length-defined K-branched ubiquitin chains to examine their binding and hydrolysis properties in vitro. Quantitatively affinity determination of ubiquitin chains to the proteasome ubiquitin receptor S5 a indicated that the S5 a exhibited preference binding to K-branched chains over K-linked chains, but not K-conjugated chains. In addition, deubiquitination experiments were carried out and the results showed that K-branched chains were preferably hydrolyzed by proteasome-associated deubiquitinase Rpnll than homotypic Kor K-linked chains.

关键词： Post-translational modification Ubiquitination K_(11,48)-branched chains Affinity deubiquitination Native chemical ligation of peptide hydrazine