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Multidimensional autophagy nano-regulator boosts Alzheimer's disease treatment by improving both extra/intraneuronal homeostasis

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1380-1399页

作者： Yixian Li Peng Yang Ran Meng Shuting Xu Lingling Zhou Kang Qian Pengzhen Wang Yunlong Cheng Dongyu Sheng Minjun Xu Tianying Wang Jing Wu Jinxu Cao Qizhi Zhang Key Laboratory of Smart Drug Delivery Ministry of EducationSchool of PharmacyFudan UniversityShanghai 201203China

Intraneuronal dysproteostasis and extraneuronal microenvironmental abnormalities in Alzheimer’s disease(AD)collectively culminate in neuronal deterioration.In the context of AD,autophagy dysfunction,a multi-link obstacle involving autophagy downregulation and lysosome defects in neurons/microglia is highly implicated in intra/extraneuronal pathological processes.Therefore,multidimensional autophagy regulation strategies co-manipulating“autophagy induction”and“lysosome degradation”in dual targets(neuron and microglia)are more reliable for AD treatment.Accordingly,we designed an RP-1 peptide-modified reactive oxygen species(ROS)-responsive micelles(RT-NM)loading rapamycin or gypenoside XVII.Guided by RP-1 peptide,the ligand of receptor for advanced glycation end products(RAGE),RT-NM efficiently targeted neurons and microglia in AD-affected region.This nanocombination therapy activated the whole autophagy-lysosome pathway by autophagy induction(rapamycin)and lysosome improvement(gypenoside XVII),thus enhancing autophagic degradation of neurotoxic aggregates and inflammasomes,and promoting Aβ phagocytosis.Resultantly,it decreased aberrant protein burden,alleviated neuroinflammation,and eventually ameliorated memory defects in 3×Tg-AD transgenic mice.Our research developed a multidimensional autophagy nano-regulator to boost the efficacy of autophagy-centered AD therapy.

关键词： Autophagy-lysosome pathway Alzheimer’s disease proteostasis Neuroinflammation Multi-target therapy Rapamycin Gypenoside XVII Cascade dual-targeting

CRL2^(APPBP2)-mediated TSPYL2 degradation counteracts human mesenchymal stem cell senescence

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Science China(Life Sciences) 2024年第3期67卷 460-474页

作者： Daoyuan Huang Qian Zhao Kuan Yang Jinghui Lei Ying Jing Hongyu Li Chen Zhang Shuai Ma Shuhui Sun Yusheng Cai Guibin Wang Jing Qu Weiqi Zhang Si Wang Guang-Hui Liu Advanced Innovation Centerfor Human Brain Protection National Clinical Research Centerfor Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Aging Translational MedicineCenter International Centerfor Aging and CancerBejing Municipal GeriatricMedical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Beijing Institute for Stem Cell and Regenerative Medicine Beijing100101China CAS Key Laboratory of Genomic and Precision Medicine Bejing Institute of Genomics and China National Center for BioinformationChinese Academy of SciencesBeijing 100101China Institute for Stem Cell and Regeneration CASBeijing 100101China The Fifth People's Hospital of Chongqing Chongqing 400062China Sino-Danish Cllege University of Chinese Academy of SciencesBeijing101408China National Laboratory of Biomacromolecules CAS Center for Excelence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing100101China State Key Laboratory of Proteomics Beijing Proteome Research CenterNational Center for Protein Sciences(Beijing)Beijing Institute of LifeomicsBeijing 102206China

Cullin-RING E3 ubiquitin ligases(CRLs),the largest family of multi-subunit E3 ubiquitin ligases in eukaryotic cells,represent core cellular machinery for executing protein degradation and maintaining proteostasis.Here,we asked what roles Cullin proteins play in human mesenchymal stem cell(hMSC)homeostasis and senescence.To this end,we conducted a comparative aging phenotype analysis by individually knocking down Cullin members in three senescence models:replicative senescent hMSCs,Hutchinson-Gilford Progeria Syndrome hMSCs,and Werner syndrome hMSCs.Among all family members,we found that CUL2 deficiency rendered hMSCs the most susceptible to senescence.To investigate CUL2-specific underlying mechanisms,we then applied CRISPR/Cas9-mediated gene editing technology to generate CUL2-deficient human embryonic stem cells(hESCs).When we differentiated these into h MSCs,we found that CUL2 deletion markedly accelerates hMSC senescence.Importantly,we identified that CUL2 targets and promotes ubiquitin proteasome-mediated degradation of TSPYL2(a known negative regulator of proliferation)through the substrate receptor protein APPBP2,which in turn downregulates one of the canonical aging marker-P21^(waf1/cip1),and thereby delays senescence.Our work provides important insights into how CRL2^(APPBP2)-mediated TSPYL2 degradation counteracts hMSC senescence,providing a molecular basis for directing intervention strategies against aging and aging-related diseases.

关键词： Cullins stem cell senescence aging proteostasis ubiquitination APPBP2 TSPYL2

Anticarin-β shows a promising antiosteosarcoma effect by specifically inhibiting CCT4 to impair proteostasis

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Acta Pharmaceutica Sinica B 2022年第5期12卷 2268-2279页

作者： Gan Wang Min Zhang Ping Meng Chengbo Long Xiaodong Luo Xingwei Yang Yunfei Wang Zhiye Zhang James Mwangi Peter Muiruri Kamau Zhi Daic Zunfu Ke Yi Zhang Wenlin Chen Xudong Zhao Fei Ge Qiumin Lv Mingqiang Rong Dongsheng Li Yang Jin Xia Sheng Ren Lai Key Laboratory of Animal Models and Human Disease Mechanisms Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan ProvinceKIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesNational Resource Center for Non-Human PrimatesKunming Primate Research Centerand National Research Facility for Phenotypic&Genetic Analysis of Model Animals(Primate Facility)Kunming Institute of ZoologyKunming 650107China University of Chinese Academy of Sciences Beijing 100049China State Key Laboratory of Phytochemistry and Plant Resources in West China Kunming Institute of BotanyChinese Academy of SciencesKunming 650201China Institutes for Drug Discovery and Development Chinese Academy of SciencesShanghai 201203China Sino-African Joint Research Center Chinese Academy of ScienceWuhan 430074China Department of Pathology First Afﬁliated HospitalSun Yat-sen UniversityGuangzhou 510080China Department of Orthopaedic Surgery First Afﬁliated Hospital of Zhengzhou UniversityZhengzhou 450052China Department of Breast Surgery Third Afﬁliated Hospital of Kunming Medical UniversityYunnan Cancer CenterKunming 650118China Department of Breast Surgery First Afﬁliated Hospital of Kunming Medical UniversityKunming 650032China Department of Biosciences University of OsloOslo 0316Norway Key Laboratory of Environment and Health Ministry of Education&Ministry of Environmental ProtectionAnd State Key Laboratory of Environmental HealthSchool of Public HealthTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 434000China Center for Biosafety Mega-Science Chinese Academy of SciencesWuhan 430071China

Unlike healthy, non-transformed cells, the proteostasis network of cancer cells is taxed to produce proteins involved in tumor development. Cancer cells have a higher dependency on molecular chaperones to maintain proteostasis. The chaperonin T-complex protein ring complex(TRiC) contains eight paralogous subunits(CCT1-8), and assists the folding of as many as 10% of cytosolic proteome.TRiC is essential for the progression of some cancers, but the roles of TRiC subunits in osteosarcoma remain to be explored. Here, we show that CCT4/TRiC is significantly correlated in human osteosarcoma,and plays a critical role in osteosarcoma cell survival. We identify a compound anticarin-β that can specifically bind to and inhibit CCT4. Anticarin-β shows higher selectivity in cancer cells than in normal cells. Mechanistically, anticarin-β potently impedes CCT4-mediated STAT3 maturation. Anticarin-β displays remarkable antitumor efficacy in orthotopic and patient-derived xenograft models of osteosarcoma.Collectively, our data uncover a key role of CCT4 in osteosarcoma, and propose a promising treatment strategy for osteosarcoma by disrupting CCT4 and proteostasis.

关键词： proteostasis CCT TRiC Osteosarcoma STAT3 Anticarin-β PDX model

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

ER exit pathways and the control of proteostasis:Crucial role of the UPR,COPII,and ER-phagy in the secretory pathway

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BIOCELL 2022年第5期46卷 1131-1137页

作者： GIUSEPPINA AMODIO VALENTINA PAGLIARA PAOLO REMONDELLI ORNELLA MOLTEDO Dipartimento di Medicina Chirurgia e Odontoiatria“Scuola Medica Salernitana”Universitàdegli Studi di SalernoBaronissi84034Italy2 Dipartimento di FarmaciaUniversitàdegli Studi di SalernoFisciano84084Italy

The endoplasmic reticulum(ER)is the site of entry of all proteins that function in the secretory pathway including the extracellular environment.Because it controls the folding of newly synthesized secretory proteins,the ER is indispensable for the maintenance of proteostasis in the secretory pathway.Within the ER and,in part,in post-ER compartments,the quality control of protein folding is under the regulation of the unfolded protein response(UPR)pathways.The UPR strategy is to enhance protein folding,increase the ER degradation pathway of misfolded proteins,and allow the exit from the ER of only correctly folded proteins.The latter is controlled by the multimeric complex COPII,which also provides some of the components for ER-phagy the only route for the disposal of protein aggregates.In this overview,we wish to contribute to the introduction of new perspectives in the study of the mechanisms underlying the control of proteostasis within the secretory pathway.

关键词： proteostasis ER stress Unfolded protein response COPII ER-phagy

Chloroplast proteostasis:A story of birth,life,and death

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维普期刊数据库

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Plant Communications 2023年第1期4卷 62-86页

作者： Lin-Lin Gao Zheng-Hui Hong Yinsong Wang Guo-Zhang Wu Shanghai Collaborative Innovation Center of Agri-Seeds School of Agriculture and BiologyShanghai Jiao Tong University800 Dongchuan RoadShanghai 200240China Joint Center for Single Cell Biology School of Agriculture and BiologyShanghai Jiao Tong University800 Dongchuan RoadShanghai 200240China

Protein homeostasis(proteostasis)is a dynamic balance of protein synthesis and degradation.Because of the endosymbiotic origin of chloroplasts and the massive transfer of their genetic information to the nucleus of the host cell,many protein complexes in the chloroplasts are constituted from subunits encoded by both genomes.Hence,the proper function of chloroplasts relies on the coordinated expression of chloroplast-and nucleus-encoded genes.The biogenesis and maintenance of chloroplast proteostasis are dependent on synthesis of chloroplast-encoded proteins,import of nucleus-encoded chloroplast proteins from the cytosol,and clearance of damaged or otherwise undesired“old”proteins.This review focuses on the regulation of chloroplast proteostasis,its interactionwith proteostasis of the cytosol,and its retrograde control over nuclear gene expression.We also discuss significant issues and perspectives for future studies and potential applications for improving the photosynthetic performance and stress tolerance of crops.

关键词： chloroplast proteostasis interaction retrograde signaling stress

Protein synthesis modulation as a therapeutic approach for amyotrophic lateral sclerosis and frontotemporal dementia

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Neural Regeneration Research 2022年第7期17卷 1423-1430页

作者： Santiago E.Charif M.Florencia Vassallu Lara Salvañal Lionel M.Igaz IFIBIO Houssay Grupo de Neurociencia de SistemasFacultad de MedicinaUniversidad de Buenos Aires-CONICETBuenos AiresArgentina

Protein synthesis is essential for cells to perform life metabolic processes.Pathological alterations of protein content can lead to particular diseases.Cells have an intrinsic array of mechanisms and pathways that are activated when protein misfolding,accumulation,aggregation or mislocalization occur.Some of them(like the unfolded protein response)represent complex interactions between endoplasmic reticulum sensors and elongation factors that tend to increase expression of chaperone proteins and/or repress translation in order to restore protein homeostasis(also known as proteostasis).This is even more important in neurons,as they are very susceptible to harmful effects associated with protein overload and proteostatic mechanisms are less effective with age.Several neurodegenerative pathologies such as Alzheimer’s,Parkinson’s,and Huntington’s diseases,amyotrophic lateral sclerosis and frontotemporal dementia exhibit a particular molecular signature of distinct,unbalanced protein overload.In amyotrophic lateral sclerosis and frontotemporal dementia,the majority of cases present intracellular inclusions of ubiquitinated transactive response DNA-binding protein of 43 kDa(TDP-43).TDP-43 is an RNA binding protein that participates in RNA metabolism,among other functions.Dysregulation of TDP-43(e.***.aggregation and mislocalization)can dramatically affect neurons,and this has been linked to disease development.Expression of amyotrophic lateral sclerosis/frontotemporal dementia TDP-43-related mutations in cellular and animal models has been shown to recapitulate key features of the amyotrophic lateral sclerosis/frontotemporal dementia disease spectrum.These variants can be causative of degeneration onset and progression.Most neurodegenerative diseases(including amyotrophic lateral sclerosis and frontotemporal dementia)have no cure at the moment;however,modulating translation has recently emerged as an attractive approach that can be performed at several steps(i.***.regulating activation of initiation and elongation factors

关键词： amyotrophic lateral sclerosis frontotemporal dementia neurodegeneration neurodegenerative diseases protein imbalance protein synthesis modulation proteostasis therapeutical compounds transactive response DNA-binding protein of 43 kDa translation unfolded protein response

Chloroplast ROS and stress signaling

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Plant Communications 2022年第1期3卷 100-114页

作者： Mengping Li Chanhong Kim Shanghai Center for Plant Stress Biology CAS Center for Excellence in Molecular Plant SciencesChinese Academy of SciencesShanghai 200032China

Chloroplasts overproduce reactive oxygen species(ROS)under unfavorable environmental conditions,and these ROS are implicated in both signaling and oxidative damage.There is mounting evidence for their roles in translating environmental fluctuations into distinct physiological responses,but their targets,signaling cascades,and mutualism and antagonism with other stress signaling cascades and within ROS signaling remain poorly understood.Great efforts made in recent years have shed new light on chloroplast ROS-directed plant stress responses,from ROS perception to plant responses,in conditional mutants of Arabidopsis thaliana or under various stress conditions.Some articles have also reported the mechanisms underlying the complexity of ROS signaling pathways,with an emphasis on spatiotemporal regulation.ROS and oxidative modification of affected target proteins appear to induce retrograde signaling pathways to maintain chloroplast protein quality control and signaling at a whole-cell level using stress hormones.This review focuses on these seemingly interconnected chloroplast-to-nucleus retrograde signaling pathways initiated by ROS and ROS-modified target molecules.We also discuss future directions in chloroplast stress research to pave the way for discovering new signaling molecules and identifying intersectional signaling components that interact in multiple chloroplast signaling pathways.

关键词： ROS ^(1)O_(2) H_(2)O_(2) oxidation operational retrograde signaling proteostasis

Interrogating the impact of aggregation-induced emission nanoparticles on in vitro protein stability,ex vivo protein homeostasis,and in vivo biocompatibility

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Aggregate

Aggregate 2022年第6期3卷 148-156页

作者： Wang Wan Qun Zhao Biao Jing Congcong Peng Mengdie Wang Yanan Huang Wenhan Jin Bowen Zhong Zhenduo Zhang Xuepeng Dong Zhenming Gao Lihua Zhang Yu Liu CAS Key Laboratory of Separation Science for Analytical Chemistry Dalian Institute of Chemical PhysicsChinese Academy of SciencesDalianChina The Second Hospital of Dalian Medical University DalianChina University of the Chinese Academy of Sciences BeijingChina

Aggregation-induced emission(AIE)materials offer promising perspectives in disease diagnosis and therapeutics given their unique optical and photochemical properties.A key step toward translational applications for AIE materials is to systematically and vigorously evaluate their biosafety and biocompatibility.While previous studies focus on cellular viability and toxicity,the impact of AIE materials on detailed stress responses manifesting cellular fitness has been less explored.Herein,this work provides the first piece of evidence to support amphiphilic functionalization of AIE nanoparticles minimizes the deterioration on proteome stability and cellular protein homeostasis(proteostasis).To this end,four scaffolds of AIE molecules were prepared,further functionalized into eight nanoparticles with two amphiphilic shells respectively,and characterized for their physicochemical properties.Thermal shift assay quantitatively demonstrates that AIE materials after amphiphilic functionalization into nanoparticles enhance proteome thermodynamic stability and ameliorate proteome aggregation propensity in cellular lysate,echoed by cell viability and fractionation experiments.Intriguingly,poor polydispersity index(PDI)of functionalized nanoparticles exaggerates their retention and aggregation in the cell.Comparative proteomic analysis uncovers that amphiphilic functionalization of AIE materials can minimize the deterioration of cellular protein homeostasis network.Finally,vigorous interrogation of functionalized AIE nanoparticles in mice model reveals the complexity of factors affecting the biocompatibility profiles in vivo,including materials’size,PDI,and treatment frequencies.Overall,amphiphilic functionalization of AIE materials into nanoparticles is necessary to maintain proteome stability and balance cellular protein homeostasis.

关键词： aggregation-induced emission biocompatibility nanoparticles protein stability proteostasis