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Decoding the Cellular Trafficking of Prion-like Proteins in Neurodegenerative Diseases

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Neuroscience Bulletin 2024年第2期40卷 241-254页

作者： Chenjun Hu Yiqun Yan Yanhong Jin Jun Yang Yongmei Xi Zhen Zhong Department of Neurology of the Second Afliated Hospital and Department of Human Anatomy Histology and EmbryologyZhejiang University School of MedicineHangzhou 310058China Department of Physiology and Department of Cardiology of the Second Afliated Hospital Zhejiang University School of MedicineHangzhou 310058China Division of Human Reproduction and Developmental Genetics Women’s Hospital and Institute of GeneticsZhejiang University School of MedicineHangzhou 310006China

The accumulation and spread of prion-like proteins is a key feature of neurodegenerative diseases(NDs)such as Alzheimer’s disease,Parkinson's disease,or Amyotrophic Lateral Sclerosis.In a process known as‘seeding’,prion-like proteins such as amyloid beta,microtubule-associated protein tau,α-synuclein,silence superoxide dismutase 1,or transactive response DNA-binding protein 43 kDa,propagate their misfolded conformations by transforming their respective soluble monomers into fibrils.Cellular and molecular evidence of prion-like propagation in NDs,the clinical relevance of their‘seeding’capacities,and their levels of contribution towards disease progression have been intensively studied over recent years.This review unpacks the cyclic prion-like propagation in cells including factors of aggregate internalization,endo-lysosomal leaking,aggregate degradation,and secretion.Debates on the importance of the role of prion-like protein aggregates in NDs,whether causal or consequent,are also discussed.Applications lead to a greater understanding of ND pathogenesis and increased potential for therapeutic strategies.

关键词： Neurodegenerative diseases Prion-like propagation Seeding endocytosis Endolyosomal leaking Degradation

Recent progress and future directions of the research on nanoplastic-induced neurotoxicity

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Neural Regeneration Research 2024年第2期19卷 331-335页

作者： Seung-Woo Han Jinhee Choi Kwon-Yul Ryu Department of Life Science University of SeoulSeoulSouth Korea School of Environmental Engineering University of SeoulSeoulSouth Korea

Many types of plastic products,including polystyrene,have long been used in commercial and industrial applications.Microplastics and nanoplastics,plastic particles derived from these plastic products,are emerging as environmental pollutants that can pose health risks to a wide variety of living organisms,including humans.However,it is not well understood how microplastics and nanoplastics affect cellular functions and induce stress responses.Humans can be exposed to polystyrene-microplastics and polystyrene-nanoplastics through ingestion,inhalation,or skin contact.Most ingested plastics are excreted from the body,but inhaled plastics may accumulate in the lungs and can even reach the brain via the nose-to-brain route.Small-sized polystyrene-nanoplastics can enter cells by endocytosis,accumulate in the cytoplasm,and cause various cellular stresses,such as inflammation with increased pro-inflammatory cytokine production,oxidative stress with generation of reactive oxygen species,and mitochondrial dysfunction.They induce autophagy activation and autophagosome formation,but autophagic flux may be impaired due to lysosomal dysfunction.Unless permanently exposed to polystyrene-nanoplastics,they can be removed from cells by exocytosis and subsequently restore cellular function.However,neurons are very susceptible to this type of stress,thus even acute exposure can lead to neurodegeneration without recovery.This review focuses specifically on recent advances in research on polystyrene-nanoplastic-induced cytotoxicity and neurotoxicity.Furthermore,in this review,based on mechanistic studies of polystyrene-nanoplastics at the cellular level other than neurons,future directions for overcoming the negative effects of polystyrene-nanoplastics on neurons were suggested.

关键词： autophagy cellular stress cytotoxicity endocytosis exocytosis inflammation microplastics nanoplastics neurotoxicity oxidative stress polystyrene

Membrane vesicles derived from Streptococcus suis serotype 2 induce cell pyroptosis in endothelial cells via the NLRP3/Caspase-1/GSDMD pathway

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Journal of Integrative Agriculture 2024年第4期23卷 1338-1353页

作者： Keda Shi Yan Li Minsheng Xu Kunli Zhang Hongchao Gou Chunling Li Shaolun Zhai Institute of Animal Health Guangdong Academy of Agricultural Sciences/Key Laboratory of Livestock Disease Prevention ofGuangdong Province/Scientific Observation and Experiment Station of Veterinary Drugs and Diagnostic Techniques of GuangdongProvinceMinistry of Agriculture and Rural AffairsGuangzhou 510640China Maoming Branch Guangdong Laboratory for Lingnan Modern Agricultural Science and TechnologyMaoming 525000China College of Animal Science&Technology Zhongkai University of Agriculture and EngineeringGuangzhou 510225China

Streptococcus suis serotype 2(S.suis 2)is a zoonotic pathogen that clinically causes severe swine and human infections(such as meningitis,endocarditis,and septicemia).In order to cause widespread diseases in different organs,S.suis 2 must colonize the host,break the blood barrier,and cause exaggerated inflammation.In the last few years,most studies have focused on a single virulence factor and its influences on the host.Membrane vesicles(MVs)can be actively secreted into the extracellular environment contributing to bacteria-host interactions.Gram-negative bacteria-derived outer membrane vesicles(OMVs)were recently shown to activate host Caspase-11-mediated non-canonical inflammasome pathway via deliverance of OMV-bound lipopolysaccharide(LPS),causing host cell pyroptosis.However,little is known about the effect of the MVs from S.suis 2(Gram-positive bacteria without LPS)on cell pyroptosis.Thus,we investigated the molecular mechanism by which S.suis 2 MVs participate in endothelial cell pyroptosis.In this study,we used proteomics,electron scanning microscopy,fluorescence microscope,Western blotting,and bioassays,to investigate the MVs secreted by S.suis 2.First,we demonstrated that S.suis 2 secreted MVs with an average diameter of 72.04 nm,and 200 proteins in MVs were identified.Then,we showed that MVs were transported to cells via mainly dynamin-dependent endocytosis.The S.suis 2 MVs activated NLRP3/Caspase-1/GSDMD canonical inflammasome signaling pathway,resulting in cell pyroptosis,but it did not activate the Caspase-4/-5 pathway.More importantly,endothelial cells produce large amounts of reactive oxygen species(ROS)and lost their mitochondrial membrane potential under induction by S.suis 2 MVs.The results in this study suggest for the first time that MVs from S.suis 2 were internalized by endothelial cells via mainly dynamin-dependent endocytosis and might promote NLRP3/Caspase-1/GSDMD pathway by mitochondrial damage,which produced mtDNA and ROS under induction,leading to the pyroptosis of endothelial cells.

关键词： Streptococcus suis serotype 2 membrane vesicles endocytosis pyroptosis NLRP3 inflammasomes mitochondrial damage endothelial cell

Monoclonal antibody targeting mu-opioid receptor attenuates morphine tolerance via enhancing morphine-induced receptor endocytosis

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Journal of Pharmaceutical Analysis 2023年第10期13卷 1135-1152页

作者： Jia-Jia Zhang Chang-Geng Song Miao Wang Gai-Qin Zhang Bin Wang Xi Chen Peng Lin Yu-Meng Zhu Zhi-Chuan Sun Ya-Zhou Wang Jian-Li Jiang Ling Li Xiang-Min Yang Zhi-Nan Chen National Translational Science Center for Molecular Medicine&Department of Cell Biology Fourth Military Medical UniversityXi'an710032China Department of Neurology Xijing HospitalFourth Military Medical UniversityXi'an710032China Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education College of Chemistry and Materials ScienceNorthwest UniversityXi'an710032China Department of Neurosurgery Xi'an Daxing HospitalXi'an710032China Department of Neurobiology and Institute of Neurosciences Collaborative Innovation Center for Brain ScienceSchool of Basic MedicineFourth Military Medical UniversityXi'an710032China

Morphine is a frequently used analgesic that activates the mu-opioid receptor(MOR),which has prominent side effects of tolerance.Although the inefficiency of morphine in inducing the endocytosis of MOR underlies the development of morphine tolerance,currently,there is no effective therapy to treat morphine tolerance.In the current study,we aimed to develop a monoclonal antibody(mAb)precisely targeting MOR and to determine its therapeutic efficacy on morphine tolerance and the underlying molecular mechanisms.We successfully prepared a mAb targeting MOR,named 3A5C7,by hybridoma technique using a strategy of deoxyribonucleic acid immunization combined with cell immunization,and identified it as an immunoglobulin G mAb with high specificity and affinity for MOR and binding ability to antigens with spatial conformation.Treatment of two cell lines,HEK293T and SH-SY5Y,with 3A5C7 enhanced morphine-induced MOR endocytosis via a G protein-coupled receptor kinase 2(GRK2)/b-arrestin2-dependent mechanism,as demonstrated by immunofluorescence staining,flow cytometry,Western blotting,coimmunoprecipitation,and small interfering ribonucleic acid(siRNA)-based knockdown.This mAb also allowed MOR recycling from cytoplasm to plasma membrane and attenuated morphine-induced phosphorylation of MOR.We established an in vitro morphine tolerance model using differentiated SH-SY5Y cells induced by retinoic acid.Western blot,enzyme-linked immunosorbent assays,and siRNA-based knockdown revealed that 3A5C7 mAb diminished hyperactivation of adenylate cyclase,the in vitro biomarker of morphine tolerance,via the GRK2/b-arrestin2 pathway.Furthermore,in vivo hotplate test demonstrated that chronic intrathecal administration of 3A5C7 significantly alleviated morphine tolerance in mice,and withdrawal jumping test revealed that both chronic and acute 3A5C7 intrathecal administration attenuated morphine dependence.Finally,intrathecal electroporation of silencing short hairpin RNA illustrated that the in vivo anti-tolerance and anti-dependence efficacy

关键词： Morphine tolerance Mu-opioid receptor endocytosis Monoclonal antibody Physical dependence

Cytoplasmic domain and enzymatic activity of ACE2 are not required for PI4KB dependent endocytosis entry of SARS-CoV-2 into host cells

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Virologica Sinica 2022年第3期37卷 380-389页

作者： Hang Yang Huijun Yuan Xiaohui Zhao Meng Xun Shangrui Guo Nan Wang Bing Liu Hongliang Wang Department of Pathogen Biology and Immunology School of Basic Medical SciencesXi'an Jiaotong University Health Science CenterXi'an710061China School of Pharmacy Xi’an Jiaotong University Health Science CenterXi'an710061China BioBank The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'an710061China Department of Life Sciences Faculty of Natural SciencesImperial College LondonLondonSW72AZUnited Kingdom Key Laboratory of Environment and Genes Related to Diseases Xi'an Jiaotong UniversityXi'an710061China

The recent COVID-19 pandemic poses a global health emergency.Cellular entry of the causative agent SARS-CoV-2 is mediated by its spike protein interacting with cellular receptor-human angiotensin converting enzyme 2(ACE2).Here,by using lentivirus based pseudotypes bearing spike protein,we demonstrated that entry of SARS-CoV-2 into host cells was dependent on clathrin-mediated endocytosis,and phosphoinositides played essential roles during this process.In addition,we showed that the intracellular domain and the catalytic activity of ACE2 were not required for efficient virus entry.Finally,we showed that the current predominant Delta variant,although with high infectivity and high syncytium formation,also entered cells through clathrin-mediated endocytosis.These results provide new insights into SARS-CoV-2 cellular entry and present proof of principle that targeting viral entry could be an effective way to treat different variant infections.

关键词： SARS-CoV-2 endocytosis Phosphoinositides Angiotensin converting enzyme 2(ACE2) Syncytium

The morphology of hydroxyapatite nanoparticles regulates clathrinmediated endocytosis in melanoma cells and resultant anti-tumor efficiency

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Nano Research 2022年第7期15卷 6256-6265页

作者： Hongfeng Wu Yuchen Hua Jinjie Wu Qin Zeng Xiao Yang Xiangdong Zhu Xingdong Zhang National Engineering Research Center for Biomaterials Sichuan UniversityChengdu 610064China NMPA Key Laboratory for Quality Research and Control of Tissue Regenerative Biomaterials&Institute of Regulatory Science for Medical Devices&NMPA Research Base of Regulatory Science for Medical Devices Sichuan UniversityChengdu 610064China Research Center for Materials Genome Engineering Sichuan UniversityChengdu 610064China

Clathrin-mediated endocytosis plays a critical role for hydroxyapatite nanoparticles(HANPs)to enter tumor cells,induce mitochondrial apoptosis,and inhibit tumor growth.This study was aimed to investigate how the morphology of HANPs impacts the endocytosis of the particles in melanoma cells,and their anti-tumor effect by using in vitro cell experiments and in vivo tumor animal model.Three shapes of HANPs,including granular HANPs(G-HANPs),rod-like HANPs(R-HANPs),and needle-like HANPs(N-HANPs),were successfully prepared by wet chemical method.All the three HANPs could be internalized into A375 melanoma cells as indicated by cellular transmission electron microscopy images.Among these HANPs,only G-HANPs induced morphological change of mitochondria and loss of mitochondrial membrane potential(Δψm),and exhibited the greatest intracellular internalization efficiency in the tumor cells.Furthermore,the results of immunofluorescence staining and western blotting indicated that the level of adaptin-2(AP2)protein was up-regulated by all the HANPs,and highest in G-HANPs treated A375 cells.Moreover,in the tumor-bearing mouse model,we found that tumor growth was delayed by all the three HANPs,of which,G-HANPs delayed tumor growth most efficiently and presented a highest expression level of AP2 protein in tumor tissues.Therefore,this study suggested that the morphology of HANPs regulated their endocytosis efficiency and their effect to inhibit tumor growth.This work facilitates to direct the rational design of nano-materials for tumor therapy.

关键词： hydroxyapatite nanoparticles adaptin-2 protein morphology endocytosis anti-tumor effect

Atomic Force Microscopy-based Cell Nanostructure for Ligand-conjugated Quantum Dot endocytosis

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Acta Biochimica et Biophysica Sinica 2006年第9期38卷 646-652页

作者： Yun-Long PAN~1* Ji-Ye CAI~2 Li QIN~3 Hao WANG~41 The First Affiliated Hospital of Jinan University,Guangzhou 510632,China 2 College of Life Science and Technology,Jinan University,Guangzhou 510632,China 3 Department of Histology and Embryology,Medical College of Jinan University,Guangzhou 510632,China 4 Information and Optoelectronic Science and Engineering.South China Normal University,Guangzhou 510631,China The First Affiliated Hospital of Jinan UniversityGuangzhou 510632 China College of Life Science and Technology Jinan UniversityGuangzhou 510632 China Department of Histology and Embryology Medical College of Jinan UniversityGuangzhou 510632 China School for Information and Optoelectronic Science and Engineering South China Normal UniversityGuangzhou 510631 China

While it has been well demonstrated that quantum dots (QDs) play an important role inbiological labeling both in vitro and in vivo,there is no report describing the cellular nanostructure basis ofreceptor-mediated endocytosis.Here,nanostructure evolution responses to the endocytosis of transferrin(Tf)-conjugated QDs were characterized by atomic force microscopy (AFM).AFM-based nanostructureanalysis demonstrated that the Tf-conjugated QDs were specifically and tightly bound to the cell receptorsand the nanostructure evolution is highly correlated with the cell membrane receptor-mediated transduction.Consistently,confocal microscopic and flow cytometry results have demonstrated the specificity anddynamic property of Tf-QD binding and internalization.We found that the internalization of Tf-QD is linearlyrelated to time.Moreover,while the nanoparticles on the cell membrane increased,the endocytosis was stillvery active,suggesting that QD nanoparticles did not interfere sterically with the binding and function ofreceptors.Therefore,ligand-conjugated QDs are potentially useful in biological labeling of cells at a nanometerscale.

关键词： quantum dot endocytosis nanostructure atomic force microscopy

Non-26S Proteasome Proteolytic Role of Ubiquitin in Plant endocytosis and Endosomal Trafficking

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Journal of Integrative Plant Biology 2013年第1期55卷 54-63页

作者： Miaomiao Tian Qi Xie State Key Laboratory of Plant Genomics National Center for Plant Gene Research Institute of Genetics and Developmental Biologythe Chinese Academy of Sciences

The 76 amino acid protein ubiquitin （Ub） is highly conserved in all eukaryotic species. It plays important roles in many cellular processes by covalently attaching to the target proteins. The best known function of Ub is marking substrate proteins for degra- dation by the 26S proteasome. In fact, other consequences of ubiquitination have been discovered in yeast and mammals, such as membrane trafficking, DNA repair, chromatin modification, and protein kinase activation. The common mechanism underlying these processes is that Ub serves as a signal to sort proteins to the vacuoles or lysosomes for degradation as opposed to 26S proteasome-dependent degradation. To date, several reports have indicated that a similar function of Ub also exists in plants. This review focuses on a summary and analysis of the recent research progress on Ub acting as a signal to mediate endocytosis and endosomal trafficking in plants.

关键词： endocytosis endosomal trafficking ubiquitin.

NUMB regulates the endocytosis and activity of the anaplastic lymphoma kinase in an isoform-specific manner

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Journal of Molecular Cell Biology 2019年第11期11卷 994-1005页

作者： Ran Wei Xuguang Liu Courtney Voss Wentao Qin Lina Dagnino Lei Li Marc Vigny Shawn Shun-Cheng Li Departments of Biochemistry Schulich School of Medicine and DentistryWestern UniversityLondonOntarioN6A 5C1Canada Dentistry Schulich School of Medicine and DentistryWestern UniversityLondonOntarioN6A 5C1Canada Physiology and Pharmacology and Schulich School of Medicine and Dentistry Western UniversityLondonOntarioN6A 5C1Canada School of Basic Medical Sciences Qingdao UniversityQingdao 266021ShandongChina Universite Pierre et Marie Curie UPMCINSERM UMRS-839ParisFrance Oncology Schulich School of Medicine and DentistryWestern UniversityLondonOntarioN6A 5C1Canada

NUMB is an evolutionarily conserved protein that plays an important role in cell adhesion,migration,polarity,and cell fate determination.It has also been shown to play a role in the pathogenesis of certain cancers,although it remains controversial whether NUMB functions as an oncoprotein or tumor suppressor.Here,we show that NUMB binds to anaplastic lymphoma kinase(ALK),a receptor tyrosine kinase aberrantly activated in several forms of cancer,and this interaction regulates the endocytosis and activity of ALK.Intriguingly,the function of the NUMB-ALK interaction is isoform-dependent.While both p66-NUMB and p72-NUMB isoforms are capable of mediating the endocytosis of ALK,the former directs ALK to the lysosomal degradation pathway,thus decreasing the overall ALK level and the downstream MAP kinase signal.In contrast,the p72-NUMB isoform promotes ALK recycling back to the plasma membrane,thereby maintaining the kinase in its active state.Our work sheds light on the controversial role of different isoforms of NUMB in tumorigenesis and provides mechanistic insight into ALK regulation.

关键词： ALK NUMB isoform endocytosis degradation recycling