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Screening of the Ubiquitin-proteasome system activators for anti-Alzheimer’s disease by the high-content fluorescence imaging system

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Chinese Journal of Natural Medicines 2022年第1期20卷 33-42页

作者： WANG Yi-Ling YOU Jing CAO Jing-Jie LI Wei JING Liu-Yang MEI Qi-Bing WU An-Guo Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia MedicaSchool of PharmacyEducation Ministry Key Laboratory of Medical ElectrophysiologySouthwest Medical UniversityLuzhou 646000China Luzhou New Drug Evaluation and Research Center Luzhou 646000China

Ubiquitin-proteasome system(UPS)plays an important role in neurodegenerative diseases,such as Alzheimer’s disease(AD),Parkinson’s disease(PD),and Huntington’s disease(HD).The discovery of UPS activators for anti-neurodegenerative diseases is becoming increasingly important.In this study,we aimed to identify potential UPS activators using the high-throughput screening method with the high-content fluorescence imaging system and validate the neuroprotective effect in the cell models of AD.At first,stable YFP-CL1 HT22 cells were successfully constructed by transfecting the YFP-CL1 plasmid into HT22 cells,together with G418 screening.The degradation activity of the test compounds via UPS was monitored by detecting the YFP fluorescence intensity reflected by the ubiquitin-proteasome degradation signal CL1.By employing the high-content fluorescence imaging system,together with stable YFP-CL1 HT22 cells,the UPS activators were successfully screened from our established TCM library.The representative images were captured and analyzed,and quantification of the YFP fluorescence intensity was performed by flow cytometry.Then,the neuroprotective effect of the UPS activators was investigated in pEGFP-N1-APP(APP),pRK5-EGFP-Tau P301L(Tau P301L),or pRK5-EGFP-Tau(Tau)transiently transfected HT22 cells using fluorescence imaging,flow cytometry,and Western blot.In conclusion,our study established a high-content fluorescence imaging system coupled with stable YFP-CL1 HT22 cells for the highthroughput screening of the UPS activators.Three compounds,namely salvianolic acid A(SAA),salvianolic acid B(SAB),and ellagic acid(EA),were identified to significantly decrease YFP fluorescence intensity,which suggested that these three compounds are UPS activators.The identified UPS activators were demonstrated to clear AD-related proteins,including APP,Tau,and Tau P301L.Therefore,these findings provide a novel insight into the discovery and development of anti-AD drugs.

关键词： Ubiquitin-proteasome system High-content fluorescence imaging system Traditional Chinese medicine Alzheimer’s disease YFP-CL1 HT22 cells

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Accelerating mutant huntingtin degradation by nanoparticles through autophagy-lysosome or Ubiquitin-proteasome system

Accelerating mutant huntingtin degradation by nanoparticles ...

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第十一届全国化学生物学学术会议

作者：魏鹏飞 Li Zhang Yunjiao Zhang Peipei Jin Long-Ping Wen 华南理工大学 Institute of Life Sciences Key Laboratory of Biomedical Engineering of Guangdong ProvinceKey Laboratory of Biomedical Materials and Engineering of the Ministry of EducationInnovation Center for Tissue Restoration and ReconstructionSouth China University of Technology National Engineering Research Center for Tissue Restoration and Reconstruction South China University of Technology

Accelerating the clearance of intracellular protein aggregates represents a viable approach for the treatment of neurodegenerative diseases.We have previously demonstrated enhanced degradation of mutant huntingtin protein aggregates through MEK/ERK1/2 signaling pathway regulated autophagy induced by europium hydroxide nanorods or graphene oxide nanoparticles. Recently,we have synthesized biocompatible MnFeO nanoparticles(NPs) and demonstrated their unique effect in accelerating the clearance of mutant huntingtin. In contrast,UPS,rather than autophagy,was responsible for the efficient mutant huntingtin degradation facilitated by MnFeO NPs.Meanwhile,we demonstrated that MnFeO NPs enhanced K48-linked ubiquitination of GFP-Htt(Q74).Moreover,ubiqinlin-1,but not p62/SQSTM1,served as the ubiquitin receptor that mediated the enhanced degradation of mutant huntingtin by MnFeO NPs. Our findings may have implications for developing novel nanomedicine for the therapy of HD and other polyglutamine expansion diseases.

关键词： Europium hydroxide nanorods Graphene oxide Autophagy-lysosomal pathway Huntington’s disease MnFe2O4 nanoparticles Polyglutamine Ubiquitin-proteasome system

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Myelinosome organelles in pathological retinas: ubiquitous presence and dual role in ocular proteostasis maintenance

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Neural Regeneration Research 2023年第5期18卷 1009-1016页

作者： Marina G.Yefimova Sechenov Institute of Evolutionary Physiology and Biochemistry Russian Academy of SciencesSt-PetersburgRussia Laboratoire STIM CNRS ERL 7003 Universitéde PoitiersPoitiersFrance

The timely and efficient elimination of aberrant proteins and damaged organelles, formed in response to various genetic and environmental stressors, is a vital need for all cells of the body. Recent lines of evidence point out several non-classical strategies employed by ocular tissues to cope with aberrant constituents generated in the retina and in the retinal pigmented epithelium cells exposed to various stressors. Along with conventional strategies relying upon the intracellular degradation of aberrant constituents through ubiquitin-proteasome and/or lysosome-dependent autophagy proteolysis, two non-conventional mechanisms also contribute to proteostasis maintenance in ocular tissues. An exosome-mediated clearing and a myelinosome-driven secretion mechanism do not require intracellular degradation but provide the export of aberrant constituents and “waste proteins” outside of the cells. The current review is centered on the non-degradative myelinosome-driven secretion mechanism, which operates in the retina of transgenic Huntington’s disease R6/1 model mice. Myelinosome-driven secretion is supported by rare organelles myelinosomes that are detected not only in degenerative Huntington’s disease R6/1 retina but also in various pathological states of the retina and of the retinal pigmented epithelium. The intra-retinal traffic and inter-cellular exchange of myelinosomes was discussed in the context of a dual role of the myelinosome-driven secretion mechanism for proteostasis maintenance in different ocular compartments. Special focus was made on the interplay between degradative and non-degradative strategies in ocular pathophysiology, to delineate potential therapeutic approaches to counteract several vision diseases.

关键词： autophagy Huntington’s disease Müller cells myelinosome-driven secretion myelinosomes ocular pathophysiology proteostasis retina retinal pigmented epithelium Ubiquitin-proteasome system

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Anticancer drug discovery by targeting cullin neddylation

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Acta Pharmaceutica Sinica B 2020年第5期10卷 746-765页

作者： Qing Yu Yihan Jiang Yi Sun Cancer Institute of the 2nd Affiliated Hospital Institute of Translational MedicineZhejiang University School of MedicineHangzhou 310029China Division of Radiation and Cancer Biology Department of Radiation OncologyUniversity of MichiganAnn ArborMI 48109.USA

Protein neddylation is a post-translational modification which transfers the ubiquitin-like protein NEDD8 to a lysine residue of the target substrate through a three-step enzymatic cascade.The bestknown substrates of neddylation are cullin family proteins,which are the core component of Cullin-RING E3 ubiquitin ligases(CRLs).Given that cullin neddylation is required for CRL activity,and CRLs control the turn-over of a variety of key signal proteins and are often abnormally activated in cancers,targeting neddylation becomes a promising approach for discovery of novel anti-cancer therapeutics.In the past decade,we have witnessed significant progress in the field of protein neddylation from preclinical target validation,to drug screening,then to the clinical trials of neddylation inhibitors.In this review,we first briefly introduced the nature of protein neddylation and the regulation of neddylation cascade,followed by a summary of all reported chemical inhibitors of neddylation enzymes.We then discussed the structure-based targeting of protein-protein interaction in neddylation cascade,and finally the available approaches for the discovery of new neddylation inhibitors.This review will provide a focused,up-to-date and yet comprehensive overview on the discovery effort of neddylation inhibitors.

关键词： Neddylation Anticancer Drug discovery Ubiquitin-proteasome system Small molecule inhibitors Virtual screen High-throughput screening

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Spatiotemporal regulation of ubiquitin-mediated protein degradation via upconversion optogenetic nanosystem

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Nano Research 2020年第12期13卷 3253-3260页

作者： Yafeng Hao Taofeng Du Gaoju Pang Jiahua Li Huizhuo Pan Yingying Zhang Lizhen Wang Jin Chang En-min Zhou Hanjie Wang School of Life Sciences Tianjin UniversityTianjin300072China Department of preventive Veterinary Medicine College of Veterinary MedicineNorthwest A&F UniversityYangling712100China

Protein degradation technology,which is one of the most direct and effective ways to regulate the life activities of cells,is expected to be applied to the treatment of various diseases.However,current protein degradation technologies such as some small-molecule degraders which are unable to achieve spatiotemporal regulation,making them difficult to transform into clinical applications.In this article,an upconversion optogenetic nanosystem was designed to attain accurate regulation of protein degradation.This system worked via two interconnected parts:1)the host cell expressed light-sensitive protein that could trigger the ubiquitinproteasome pathway upon blue-light exposure;2)the light regulated light-sensitive protein by changing light conditions to achieve regulation of protein degradation.Experimental results based on model protein(Green Fluorescent Protein,GFP)validated that this system could fulfill protein degradation both in vitro(both Hela and 293T cells)and in vivo(by upconversion optogenetic nanosystem),and further demonstrated that we could reach spatiotemporal regulation by changing the illumination time(0–25 h)and the illumination frequency(the illuminating frequency of 0–30 s every 1 min).We further took another functional protein(The Nonstructural Protein 9,NSP9)into experiment.Results confirmed that the proliferation of porcine reproductive and respiratory syndrome virus(PRRSV)was inhibited by degrading the NSP9 in this light-induced system,and PRRSV proliferation was affected by different light conditions(illumination time varies from 0–24 h).We expected this system could provide new perspectives into spatiotemporal regulation of protein degradation and help realize the clinical application transformation for treating diseases of protein degradation technology.

关键词： protein degradation Ubiquitin-proteasome system optogenetics upconversion materials the nonstructural protein9(NSP9) porcine reproductive and respiratory syndrome virus(PRRSV)

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A Bunyavirus-Inducible ubiquitin Ligase Targets RNA Polymerase IV for Degradation during Viral Pathogenesis in Rice

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Molecular Plant 2020年第6期13卷 836-850页

作者： Chao Zhang Ying Wei Le Xu Kang-Cheng Wu Liang Yang Chao-Nan Shi Guo-Yi Yang Dong Chen Fei-Fei Yu Qi Xie Shou-Wei Ding Jian-Guo Wu Vector-borne Virus Research Center Key Laboratory of Plant Virology of Fujian ProvinceInstitute of Plant VirologyCollege of Plant ProtectionFujian Agriculture and Forestry UniversityFuzhou 350002China Center for Plant Biology Tsinghua-Peking Center for Life SciencesCollege of Life SciencesTsinghua UniversityBeijing 100084China State Key Laboratory of Plant Genomics National Center for Plant Gene ResearchInstitute of Genetics and Developmental BiologyChinese Academy of SciencesBeijing 100101China Department of Microbiology and Plant Pathology and Center for Plant Cell Biology Institute for Integrative Genome BiologyUniversity of CaliforniaRiversideCA92521USA

The Ubiquitin-proteasome system(UPS)is an important post-translational regulatory mechanism that controls many cellular functions in eukaryotes.Here,we show that stable expression of P3 protein encoded by Rice grassy stunt virus(RGSV),a negative-strand RNA virus in the Bunyavirales,causes developmental abnormities similar to the disease symptoms caused by RGSV,such as dwarfing and excess tillering,in transgenic rice plants.We found that both transgenic expression of P3 and RGSV infection induce ubiquitination and UPS-dependent degradation of rice NUCLEAR RNA POLYMERASE D1a(OsNRPD1a),one of two orthologs of the largest subunit of plant-specific RNA polymerase IV(Pol IV),which is required for RNA-directed DNA methylation(RdDM).Furthermore,we identified a P3-inducible U-box type E3 ubiquitin ligase,designated as P3-inducible protein 1(P3IP1),which interacts with OsNRPD1a and mediates its ubiquitination and UPS-dependent degradation in vitro and in vivo.Notably,both knockdown of OsNRPD1 and overexpression of P3IP1 in rice plants induced developmental phenotypes similar to RGSV disease symptomss.Taken together,our findings reveal a novel virulence mechanism whereby plant pathogens target host RNA Pol IV for UPS-dependent degradation to induce disease symptoms.Our study also identified an E3 ubiquitin ligase,which targets the RdDM compotent NRPD1 for UPS-mediated degradation in rice.

关键词： Ubiquitin-proteasome system NRPD1 Rice grassy stunt virus E3 ligase

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The E3 ubiquitin ligase HUWE1 acts through the N-Myc-DLL1-NOTCH1 signaling axis to suppress glioblastoma progression

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Cancer Communications 2022年第9期42卷 868-886页

作者： Ye Yuan Li-Hong Wang Xian-Xian Zhao Jiao Wang Meng-Si Zhang Qing-Hua Ma Sen Wei Ze-Xuan Yan Yue Cheng Xiao-Qing Chen Hong-Bo Zou Jia Ge Yan Wang Xia Zhang You-Hong Cui Tao Luo Xiu-Wu Bian Institute of Pathology and Southwest Cancer Center Southwest HospitalThird Military Medical University(Army Medical University)and Key Laboratory of Tumor ImmunopathologyMinistry of Education of ChinaChongqing 400038P.R.China Bio-Bank of Southwest Hospital Third Military Medical University(Army Medical University)Chongqing 400038P.R.China Department of Clinical Laboratory Southwest HospitalThird Military Medical University(Army Medical University)Chongqing 400038P.R.China Department of Oncology the Third Affiliated Hospital of Chongqing Medical UniversityChongqing 401120P.R.China

Background:Elucidation of the post-transcriptional modification has led to novel strategies to treat intractable tumors,especially glioblastoma(GBM).The Ubiquitin-proteasome system(UPS)mediates a reversible,stringent and stepwise post-translational modification which is closely associated with malignant processes of GBM.To this end,developing novel therapeutic approaches to target the UPS may contribute to the treatment of this disease.This study aimed to screen the vital and aberrantly regulated component of the UPS in GBM.Based on the molecular identification,functional characterization,and mechanism investigation,we sought to elaborate a novel therapeutic strategy to target this vital factor to combat GBM.Methods:We combined glioma datasets and human patient samples to screen and identify aberrantly regulated E3 ubiquitin ligase.Multidimensional database analysis and molecular and functional experiments in vivo and in vitro were used to evaluate the roles of HECT,UBA and WWE domain-containing E3 ubiquitin ligase 1(HUWE1)in GBM.dCas9 synergistic activation mediator system and recombinant adeno-associated virus(rAAV)were used to endogenously overexpress full-length HUWE1 in vitro and in glioma orthotopic xenografts.Results:Low expression of HUWE1 was closely associated with worse prognosis of GBM patients.The ubiquitination and subsequent degradation of N-Myc mediated by HUWE1,leading to the inactivation of downstream Delta-like 1(DLL1)-NOTCH1 signaling pathways,inhibited the proliferation,invasion,and migration of GBM cells in vitro and in vivo.A rAAV dual-vector system for packaging and delivery of dCas9-VP64 was used to augment endogenous HUWE1 expression in vivo and showed an antitumor activity in glioma orthotopic xenografts.Conclusions:The E3 ubiquitin ligase HUWE1 acts through the N-Myc-DLL1-NOTCH1 signaling axis to suppress GBM progression.Antitumor activity of rAAV dual-vector delivering dCas9-HUWE1 system uncovers a promising therapeutic strategy for GBM.

关键词： DLL1 E3 ubiquitin ligase glioblastoma HUWE1 N-Myc NOTCH1 recombinant adenoassociated virus Ubiquitin-proteasome system

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Anchanling reduces pathology in a lactacystin-induced Parkinson's disease model

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Neural Regeneration Research 2012年第3期7卷 165-170页

作者： Yinghong Li Zhengzhi Wu Xiaowei Gao Qingwei Zhu Yu Jin Anmin Wu Andrew C. J.Huang Shenzhen Second People＇s Hospital First Affiliated Hospital of Shenzhen University Shenzhen 518035 Guangdong Province China Shenzhen Institute of Gerontology Second Clinical Medical College Jinan University Shenzhen 518020 Guangdong Province China Larry Hillblom Islet Research Center David Geffen School of Medicine UCLA Los Angeles CA 90024 USA

A rat model of Parkinson＇s disease was induced by injecting lactacystin stereotaxically into the left mesencephalic ventral tegmental area and substantia nigra pars compacta. After rats were intragastrically perfused with Anchanling, a Chinese medicine, mainly composed of magnolol, for 5 weeks, when compared with Parkinson’s disease model rats, tyrosine hydroxylase expression was increased, α-synuclein and ubiquitin expression was decreased, substantia nigra cell apoptosis was reduced, and apomorphine-induced rotational behavior was improved. Results suggested that Anchanling can ameliorate Parkinson＇s disease pathology possibly by enhancing degradation activity of the Ubiquitin-proteasome system.

关键词： Parkinson＇s disease Anchanling Ubiquitin-proteasome system α-synuclein tyrosine hydroxylase cell apoptosis

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Putting it all together： intrinsic and extrinsic mechanisms governing proteasome biogenesis

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Frontiers in Biology 2017年第1期12卷 19-48页

作者： Lauren A. Howell Robert J. Tomko Jr. Andrew R. Kusmierczyk Department of Biomedical Sciences Florida State University College of Medicine Tallahassee FL 32306 USA Department of Biology Indiana University-Purdue Universi~ Indianapolis Indianapolis IN 46202 USA

BACKGROUND： The 26S proteasome is at the heart of the Ubiquitin-proteasome system, which is the key cellular pathway for the regulated degradation of proteins and enforcement of protein quality control. The 26S proteasome is an unusually large and complicated protease comprising a 28-subunit core particle （CP） capped by one or two 19-subunit regulatory particles （RP）. Multiple activities within the RP process incoming ubiquitinated substrates for eventual degradation by the barrel-shaped CE The large size and elaborate architecture of the proteasome have made it an exceptional model for understanding mechanistic themes in macromolecular assembly. OBJECTIVE： In the present work, we highlight the most recent mechanistic insights into proteasome assembly, with particular emphasis on intrinsic and extrinsic factors regulating proteasome biogenesis. We also describe new and exciting questions arising about how proteasome assembly is regulated and deregulated in normal and diseased cells. METHODS： A comprehensive literature search using the PubMed search engine was performed, and key findings yielding mechanistic insight into proteasome assembly were included in this review. RESULTS： Key recent studies have revealed that proteasome biogenesis is dependent upon intrinsic features of the subunits themselves as well as extrinsic factors, many of which function as dedicated chaperones. CONCLUSION： Cells rely on a diverse set of mechanistic strategies to ensure the rapid, efficient, and faithful assembly of proteasomes from their cognate subunits. Importantly, physiological as well as pathological changes to proteasome assembly are emerging as exciting paradigms to alter protein degradation in vivo.

关键词： proteasome assembly assembly chaperones Ubiquitin-proteasome system proteolysis macromolecular complex

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Oxidative modification of the molecular chaperone family in a PC12 cell model of Parkinson's disease induced by Z-Ile-Glu(OtBu)-Ala-Leucinal

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Neural Regeneration Research 2011年第2期6卷 85-90页

作者： Ying Zhang Yimin Yang Jing Bai Ming Chang Linsen Hu Department of Neurology First Hospital of Jilin University Changchun 130021 Jilin Province China Department of ICU First Hospital of Jilin University Changchun 130021 Jilin Province China

Previous studies have demonstrated that Ubiquitin-proteasome system function is significantly decreased in the substantia nigra of Parkinson＇s disease patients. In the present study, proteasome inhibitor Z-Ile-Glu（OtBu）-Ala-Leucinal （PSI） was used to inhibit the function of the Ubiquitin-proteasome system in PC12 cells to simulate Parkinson＇s disease. Oxidatively modified proteins were identified to determine pathogenesis of Parkinson＇s disease. Results demonstrated that 24 hours of 10 IJmol/L PSI-treatment in PC12 cells simulated pathological characteristics of Parkinson＇s disease： neuronal degeneration and eosinophilic inclusion formation in neurons. In PSI-treated PC12 cells, three oxidative proteins and a molecular chaperone family member were detected： chaperonin containing t-complex polypeptide 1 subunit 3, glucose-regulated protein 58, and heat shock protein 70. This is the first study to demonstrate oxidative modification of a molecule family in a cell model of Parkinson＇s disease induced with PSI.

关键词： molecular chaperones pathogenesis proteomics protein arbonylation Parkinson＇s disease Ubiquitin-proteasome system

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