Stroke-induced immunosuppression is a process that leads to peripheral suppression of the immune system after a stroke and belongs to the central nervous system injury-induced immunosuppressive syndrome.Stroke-induced...Stroke-induced immunosuppression is a process that leads to peripheral suppression of the immune system after a stroke and belongs to the central nervous system injury-induced immunosuppressive syndrome.Stroke-induced immunosuppression leads to increased susceptibility to post-stroke infections,such as urinary tract infections and stroke-associated pneumonia,worsening prognosis.Molecular chaperones are a large class of proteins that are able to maintain proteostasis by directing the folding of nascent polypeptide chains,refolding misfolded proteins,and targeting misfolded proteins for degradation.Various molecular chaperones have been shown to play roles in stroke-induced immunosuppression by modulating the activity of other molecular chaperones,cochaperones,and their associated pathways.This review summarizes the role of molecular chaperones in stroke-induced immunosuppression and discusses new approaches to restore host immune defense after stroke.展开更多
Protein folding in crowding cellular environment often relies on the assistance of various chaperones. Hsp70 is one of the most ubiquitous chaperones in cells. Previous studies showed that the chaperone–client intera...Protein folding in crowding cellular environment often relies on the assistance of various chaperones. Hsp70 is one of the most ubiquitous chaperones in cells. Previous studies showed that the chaperone–client interactions at the open state tend to remodel the protein folding energy landscape and direct the protein folding as a foldase. In this work, we further investigate how the chaperone–client interaction strength modulates the foldase function of Hsp70 by using molecular simulations. The results showed that the time of substrate folding(including the whole folding step and substrate release step) has a non-monotonic dependence on the interaction strength. With the increasing of the chaperone–client interaction strength, the folding time decreases first, and then increases. More detailed analysis showed that when the chaperone–client interaction is too strong, even small number of chaperones–client contacts can maintain the substrate bound with the chaperone. The sampling of the transient chaperones–client complex with sparse inter-molecule contacts makes the client protein have chance to access the misfolded state even it is bound with chaperone. The current results suggest that the interaction strength is an important factor controlling the Hsp70 chaperoning function.展开更多
Parkinson's disease(PD) is one of the most debilitating brain diseases. Despite the availability of symptomatic treatments, response towards the health of PD patients remains scarce. To fulfil the medical needs of...Parkinson's disease(PD) is one of the most debilitating brain diseases. Despite the availability of symptomatic treatments, response towards the health of PD patients remains scarce. To fulfil the medical needs of the PD patients, an efficacious and etiological treatment is required. In this review, we have compiled the information covering limitations of current therapeutic options in PD, novel drug targets for PD, and finally, the role of some critical beneficial natural products to control the progression of PD.展开更多
Bemisia tabaci (Gennadius) (Homoptera: Aleyrodidae) is the most destructive invasive pests in agricultural production and has a high tolerance to heat. Heat shock proteins play an essential role in life activities suc...Bemisia tabaci (Gennadius) (Homoptera: Aleyrodidae) is the most destructive invasive pests in agricultural production and has a high tolerance to heat. Heat shock proteins play an essential role in life activities such as growth and development, reproduction and diapause of B. tabaci. At the same time, they are also crucial in resisting adverse environments and in adaptive evolution. The expression of heat shock protein in B. tabaci is not only related to temperature, but also to the tolerance of the environment. After receiving external stimuli, the expression level can be increased or decreased to maintain the stability of cells in vivo. This paper reviews the classification, biological characteristics, biological functions, and research status of HSPs in recent years. This mini-review will provide helpful information related to the use of heat shock proteins to study the occurrence and damage of B. tabaci. This has important theoretical and practical significance for revealing Hsps in explaining the population expansion mechanism of B. tabaci invasion and predicting population dynamics.展开更多
We describe and discuss the most recent findings on the activity and function of the oligomeric AAA+ chaperone ClpB from the Hsp100 protein family in pathogenic microorganisms. Pathogens are exposed to significant str...We describe and discuss the most recent findings on the activity and function of the oligomeric AAA+ chaperone ClpB from the Hsp100 protein family in pathogenic microorganisms. Pathogens are exposed to significant stress during infection of the host cells, frequently resulting in protein aggregation. The fact that ClpB is usually up-regulated in pathogens together with its immune reactivity suggests that ClpB acting as a protein disaggregase may be important for pathogen invasion and virulence. However, the specific function of ClpB in pathogenicity is still unclear. Since it is known that ClpB does not exist in mammals, it may serve as a potential target for the development of an effective therapy against several major bacterial diseases that do not respond to conventional antibiotics.展开更多
Gradual degeneration and loss of dopaminergic neurons in the substantia nigra,pars compacta and subsequent reduction of dopamine levels in striatum are associated with motor deficits that characterize Parkinson’s dis...Gradual degeneration and loss of dopaminergic neurons in the substantia nigra,pars compacta and subsequent reduction of dopamine levels in striatum are associated with motor deficits that characterize Parkinson’s disease(PD).In addition,half of the PD patients also exhibit frontostriatal-mediated executive dysfunction,including deficits in attention,short-term working memory,speed of mental processing,and impulsivity.The most commonly used treatments for PD are only partially or transiently effective and are available or applicable to a minority of patients.Because,these therapies neither restore the lost or degenerated dopaminergic neurons,nor prevent or delay the disease progression,the need for more effective therapeutics is critical.In this review,we provide a comprehensive overview of the current understanding of the molecular signaling pathways involved in PD,particularly within the context of how genetic and environmental factors contribute to the initiation and progression of this disease.The involvement of molecular chaperones,autophagy-lysosomal pathways,and proteasome systems in PD are also highlighted.In addition,emerging therapies,including pharmacological manipulations,surgical procedures,stem cell transplantation,gene therapy,as well as complementary,supportive and rehabilitation therapies to prevent or delay the progression of this complex disease are reviewed.展开更多
The presence of protein aggregates in numerous human diseases underscores the significance of detecting these aggregates to comprehend disease mechanisms and develop novel therapeutic approaches for combating these di...The presence of protein aggregates in numerous human diseases underscores the significance of detecting these aggregates to comprehend disease mechanisms and develop novel therapeutic approaches for combating these disorders.Despite the development of various biosensors and fluorescent probes that selectively target amyloid fibers or amorphous aggregates,there is still a lack of tools capable of simultaneously detecting both types of aggregates.Herein,we demonstrate the quantitative discernment of amorphous aggregates by QM-FN-SO3,an aggregationinduced emission(AIE)probe initially designed for detecting amyloid fibers.This probe easily penetrates the membranes of the widely-used prokaryotic model organism Escherichia coli,enabling the visualization of both amorphous aggregates and amyloid fibers through near-infrared fluorescence.Notably,the probe exhibits sensitivity in distinguishing the varying aggregation propensities of proteins,regardless of whether they form amorphous aggregates or amyloid fibers in vivo.These properties contribute to the successful application of the QM-FN-SO3 probe in the subsequent investigation of the antiaggregation activities of two outer membrane protein(OMP)chaperones,both in vitro and in their physiological environment.Overall,our work introduces a near-infrared fluorescent chemical probe that can quantitatively detect amyloid fibers and amorphous aggregates with high sensitivity in vitro and in vivo.Furthermore,it demonstrates the applicability of the probe in chaperone biology and its potential as a high-throughput screening tool for protein aggregation inhibitors and folding factors.展开更多
Modulation of protein fate decision and protein homeostasis plays a significant role in altering the protein level,which acts as an orientation to develop drugs with new mechanisms.The molecular chaperones exert signi...Modulation of protein fate decision and protein homeostasis plays a significant role in altering the protein level,which acts as an orientation to develop drugs with new mechanisms.The molecular chaperones exert significant biological functions on modulation of protein fate decision and protein homeostasis under constantly changing environmental conditions through extensive protein-protein interactions(PPIs)with their client proteins.With the help of molecular chaperone machinery the processes of protein folding,trafficking,quality control and degradation of client proteins could be arranged properly.The core members of molecular chaperones,including heat shock proteins(HSPs)family and their co-chaperones,are emerging as potential drug targets since they are involved in numerous disease conditions.Development of small molecule modulators targeting not only chaperones themselves but also the PPIs among chaperones,co-chaperones and clients is attracting more and more attention.These modulators are widely used as chemical tools to study chaperone networks as well as potential drug candidates for a broader set of diseases.Here,we reviewed the key checkpoints of molecular chaperone machinery HSPs as well as their co-chaperones to discuss the small molecules targeting on them for modulation of protein fate decision.展开更多
DNA cytosine methylation confers stable epigenetic silencing in plants and many animals.However,the mechanisms underlying DNA methylation-mediated genomic silencing are not fully understood.We conducted a forward gene...DNA cytosine methylation confers stable epigenetic silencing in plants and many animals.However,the mechanisms underlying DNA methylation-mediated genomic silencing are not fully understood.We conducted a forward genetic screen for cellular factors required for the silencing of a heavily methylated p35S:NPTII transgene in the Arabidopsis thaliana rdm1-1 mutant background,which led to the identification of a Hsp20 family protein,RDS1(rdm1-1 suppressor 1).Loss-of-function mutations in RDS1 released the silencing of the p35S::NPTII transgene in rdm1-1 mutant plants,without changing the DNA methylation state of the transgene.Protein interaction analyses suggest that RDS1 exists in a protein complex consisting of the methyl-DNA binding domain proteins MBD5 and MBD6,two other Hsp20 family proteins,RDS2 and IDM3,a Hsp40/DNAJ family protein,and a Hsp70 family protein.Like rds1 mutations,mutations in RDS2,MBD5,or MBD6 release the silencing of the transgene in the rdm1 mutant background.Our results suggest that Hsp20,Hsp40,and Hsp70 proteins may form a complex that is recruited to some genomic regions with DNA methylation by methyl-DNA binding proteins to regulate the state of silencing of these regions.展开更多
Subcellular organelles in eukaryotes are surrounded by lipid membranes.In an endomembrane system,vesicle trafficking is the primary mechanism for the delivery of organellar proteins to specific organelles.However,orga...Subcellular organelles in eukaryotes are surrounded by lipid membranes.In an endomembrane system,vesicle trafficking is the primary mechanism for the delivery of organellar proteins to specific organelles.However,organellar proteins for chloroplasts,mitochondria,the nucleus,and peroxisomes that are translated in the cytosol are directly imported into their target organelles.Chloroplasts are a plant-specific organelle with outer and inner envelope membranes,a dual-membrane structure that is similar to mitochondria.Interior chloroplast proteins translated by cytosolic ribosomes are thus translocated through TOC and TIC complexes(translocons in the outer and inner envelope of chloroplasts,respectively),with stromal ATPase motor proteins playing a critical role in pulling pre-proteins through these import channels.Over the last three decades,the identity and function of TOC/TIC components and stromal motor proteins have been actively investigated,which has shed light on the action mechanisms at a molecular level.However,there remains some disagreement over the exact composition of TIC complexes and genuine stromal motor proteins.In this review,we discuss recent findings on the mechanisms by which proteins are translocated through TOC/TIC complexes and discuss future prospects for this field of research.展开更多
基金the National Natural Science Foundation of China,Nos.82172147(to YL),81571880(to YL),81373147(to YL),30901555(to JZ),30972870(to YL)the Natural Science Foundation of Hunan Province,Nos.2021JJ30900,2016JJ2157(both to YL)。
文摘Stroke-induced immunosuppression is a process that leads to peripheral suppression of the immune system after a stroke and belongs to the central nervous system injury-induced immunosuppressive syndrome.Stroke-induced immunosuppression leads to increased susceptibility to post-stroke infections,such as urinary tract infections and stroke-associated pneumonia,worsening prognosis.Molecular chaperones are a large class of proteins that are able to maintain proteostasis by directing the folding of nascent polypeptide chains,refolding misfolded proteins,and targeting misfolded proteins for degradation.Various molecular chaperones have been shown to play roles in stroke-induced immunosuppression by modulating the activity of other molecular chaperones,cochaperones,and their associated pathways.This review summarizes the role of molecular chaperones in stroke-induced immunosuppression and discusses new approaches to restore host immune defense after stroke.
基金Project supported by the National Natural Science Foundation of China (Grant Nos. 11305139 and 11974173)the HPC Center of Nanjing University。
文摘Protein folding in crowding cellular environment often relies on the assistance of various chaperones. Hsp70 is one of the most ubiquitous chaperones in cells. Previous studies showed that the chaperone–client interactions at the open state tend to remodel the protein folding energy landscape and direct the protein folding as a foldase. In this work, we further investigate how the chaperone–client interaction strength modulates the foldase function of Hsp70 by using molecular simulations. The results showed that the time of substrate folding(including the whole folding step and substrate release step) has a non-monotonic dependence on the interaction strength. With the increasing of the chaperone–client interaction strength, the folding time decreases first, and then increases. More detailed analysis showed that when the chaperone–client interaction is too strong, even small number of chaperones–client contacts can maintain the substrate bound with the chaperone. The sampling of the transient chaperones–client complex with sparse inter-molecule contacts makes the client protein have chance to access the misfolded state even it is bound with chaperone. The current results suggest that the interaction strength is an important factor controlling the Hsp70 chaperoning function.
基金supported by UGC Dr.D.S.Kothari Postdoctoral scheme by awarding the fellowship to SNR(Ref.No-F.4-2/2006(BSR)/BL/19-20/0032)。
文摘Parkinson's disease(PD) is one of the most debilitating brain diseases. Despite the availability of symptomatic treatments, response towards the health of PD patients remains scarce. To fulfil the medical needs of the PD patients, an efficacious and etiological treatment is required. In this review, we have compiled the information covering limitations of current therapeutic options in PD, novel drug targets for PD, and finally, the role of some critical beneficial natural products to control the progression of PD.
文摘Bemisia tabaci (Gennadius) (Homoptera: Aleyrodidae) is the most destructive invasive pests in agricultural production and has a high tolerance to heat. Heat shock proteins play an essential role in life activities such as growth and development, reproduction and diapause of B. tabaci. At the same time, they are also crucial in resisting adverse environments and in adaptive evolution. The expression of heat shock protein in B. tabaci is not only related to temperature, but also to the tolerance of the environment. After receiving external stimuli, the expression level can be increased or decreased to maintain the stability of cells in vivo. This paper reviews the classification, biological characteristics, biological functions, and research status of HSPs in recent years. This mini-review will provide helpful information related to the use of heat shock proteins to study the occurrence and damage of B. tabaci. This has important theoretical and practical significance for revealing Hsps in explaining the population expansion mechanism of B. tabaci invasion and predicting population dynamics.
文摘We describe and discuss the most recent findings on the activity and function of the oligomeric AAA+ chaperone ClpB from the Hsp100 protein family in pathogenic microorganisms. Pathogens are exposed to significant stress during infection of the host cells, frequently resulting in protein aggregation. The fact that ClpB is usually up-regulated in pathogens together with its immune reactivity suggests that ClpB acting as a protein disaggregase may be important for pathogen invasion and virulence. However, the specific function of ClpB in pathogenicity is still unclear. Since it is known that ClpB does not exist in mammals, it may serve as a potential target for the development of an effective therapy against several major bacterial diseases that do not respond to conventional antibiotics.
文摘Gradual degeneration and loss of dopaminergic neurons in the substantia nigra,pars compacta and subsequent reduction of dopamine levels in striatum are associated with motor deficits that characterize Parkinson’s disease(PD).In addition,half of the PD patients also exhibit frontostriatal-mediated executive dysfunction,including deficits in attention,short-term working memory,speed of mental processing,and impulsivity.The most commonly used treatments for PD are only partially or transiently effective and are available or applicable to a minority of patients.Because,these therapies neither restore the lost or degenerated dopaminergic neurons,nor prevent or delay the disease progression,the need for more effective therapeutics is critical.In this review,we provide a comprehensive overview of the current understanding of the molecular signaling pathways involved in PD,particularly within the context of how genetic and environmental factors contribute to the initiation and progression of this disease.The involvement of molecular chaperones,autophagy-lysosomal pathways,and proteasome systems in PD are also highlighted.In addition,emerging therapies,including pharmacological manipulations,surgical procedures,stem cell transplantation,gene therapy,as well as complementary,supportive and rehabilitation therapies to prevent or delay the progression of this complex disease are reviewed.
基金Natural Science Foundation of Shanghai,Grant/Award Number:23ZR1415300National Natural Science Foundation of China,Grant/Award Numbers:32222049,31661143021,32171269,32201043+1 种基金National Key Research and Development Program of China,Grant/Award Number:2022YFF1102900Shanghai Frontier Science Center of Optogenetic Techniques for Cell Metabolism Shanghai Municipal Education Commission,Grant/Award Number:2021Sci&Tech0328。
文摘The presence of protein aggregates in numerous human diseases underscores the significance of detecting these aggregates to comprehend disease mechanisms and develop novel therapeutic approaches for combating these disorders.Despite the development of various biosensors and fluorescent probes that selectively target amyloid fibers or amorphous aggregates,there is still a lack of tools capable of simultaneously detecting both types of aggregates.Herein,we demonstrate the quantitative discernment of amorphous aggregates by QM-FN-SO3,an aggregationinduced emission(AIE)probe initially designed for detecting amyloid fibers.This probe easily penetrates the membranes of the widely-used prokaryotic model organism Escherichia coli,enabling the visualization of both amorphous aggregates and amyloid fibers through near-infrared fluorescence.Notably,the probe exhibits sensitivity in distinguishing the varying aggregation propensities of proteins,regardless of whether they form amorphous aggregates or amyloid fibers in vivo.These properties contribute to the successful application of the QM-FN-SO3 probe in the subsequent investigation of the antiaggregation activities of two outer membrane protein(OMP)chaperones,both in vitro and in their physiological environment.Overall,our work introduces a near-infrared fluorescent chemical probe that can quantitatively detect amyloid fibers and amorphous aggregates with high sensitivity in vitro and in vivo.Furthermore,it demonstrates the applicability of the probe in chaperone biology and its potential as a high-throughput screening tool for protein aggregation inhibitors and folding factors.
基金the financial support by National Natural Science Foundation of China(81773639,81773581,81872737 and 81930100)the Natural Science Foundation of Jiangsu Province(BK20190559,BK20160746 China)+6 种基金National Science&Technology Major Project‘Key New Drug Creation and Manufacturing Program’(Nos.2018ZX09711002 and 2017ZX09302003,China)the Priority Academic Program Development of Jiangsu Higher Education Institutionsthe Fundamental Research Funds for the Central Universities of China Pharmaceutical University(2632018ZD15,China)the Double First Class Innovation Team of China Pharmaceutical University(CPU2018GY02,China)Program for Outstanding Scientific and Technological Innovation Team of Jiangsu Higher Educationthe Young Elite Scientists Sponsorship Program by CASTthe Jiangsu Qing Lan Project
文摘Modulation of protein fate decision and protein homeostasis plays a significant role in altering the protein level,which acts as an orientation to develop drugs with new mechanisms.The molecular chaperones exert significant biological functions on modulation of protein fate decision and protein homeostasis under constantly changing environmental conditions through extensive protein-protein interactions(PPIs)with their client proteins.With the help of molecular chaperone machinery the processes of protein folding,trafficking,quality control and degradation of client proteins could be arranged properly.The core members of molecular chaperones,including heat shock proteins(HSPs)family and their co-chaperones,are emerging as potential drug targets since they are involved in numerous disease conditions.Development of small molecule modulators targeting not only chaperones themselves but also the PPIs among chaperones,co-chaperones and clients is attracting more and more attention.These modulators are widely used as chemical tools to study chaperone networks as well as potential drug candidates for a broader set of diseases.Here,we reviewed the key checkpoints of molecular chaperone machinery HSPs as well as their co-chaperones to discuss the small molecules targeting on them for modulation of protein fate decision.
基金This work was supported by the Strategic Priority Research Program(grant XDB27040101 to J.-K.Z.)of the Chinese Academy of Sciences,and the Key Research and Development Plan of Shaanxi Province(grant No.2020ZDLNY01-03 to X.Z.).
文摘DNA cytosine methylation confers stable epigenetic silencing in plants and many animals.However,the mechanisms underlying DNA methylation-mediated genomic silencing are not fully understood.We conducted a forward genetic screen for cellular factors required for the silencing of a heavily methylated p35S:NPTII transgene in the Arabidopsis thaliana rdm1-1 mutant background,which led to the identification of a Hsp20 family protein,RDS1(rdm1-1 suppressor 1).Loss-of-function mutations in RDS1 released the silencing of the p35S::NPTII transgene in rdm1-1 mutant plants,without changing the DNA methylation state of the transgene.Protein interaction analyses suggest that RDS1 exists in a protein complex consisting of the methyl-DNA binding domain proteins MBD5 and MBD6,two other Hsp20 family proteins,RDS2 and IDM3,a Hsp40/DNAJ family protein,and a Hsp70 family protein.Like rds1 mutations,mutations in RDS2,MBD5,or MBD6 release the silencing of the transgene in the rdm1 mutant background.Our results suggest that Hsp20,Hsp40,and Hsp70 proteins may form a complex that is recruited to some genomic regions with DNA methylation by methyl-DNA binding proteins to regulate the state of silencing of these regions.
基金supported by an NRF grant funded by the MSIT(grant NRF-2020R1A2C4002294)supported by a National Research Foundation of Korea(NRF)grant funded by the Korean government(MSIT)(No.2019R1A2B5B03099982)。
文摘Subcellular organelles in eukaryotes are surrounded by lipid membranes.In an endomembrane system,vesicle trafficking is the primary mechanism for the delivery of organellar proteins to specific organelles.However,organellar proteins for chloroplasts,mitochondria,the nucleus,and peroxisomes that are translated in the cytosol are directly imported into their target organelles.Chloroplasts are a plant-specific organelle with outer and inner envelope membranes,a dual-membrane structure that is similar to mitochondria.Interior chloroplast proteins translated by cytosolic ribosomes are thus translocated through TOC and TIC complexes(translocons in the outer and inner envelope of chloroplasts,respectively),with stromal ATPase motor proteins playing a critical role in pulling pre-proteins through these import channels.Over the last three decades,the identity and function of TOC/TIC components and stromal motor proteins have been actively investigated,which has shed light on the action mechanisms at a molecular level.However,there remains some disagreement over the exact composition of TIC complexes and genuine stromal motor proteins.In this review,we discuss recent findings on the mechanisms by which proteins are translocated through TOC/TIC complexes and discuss future prospects for this field of research.
