Hepatic stellate cells(HSCs)are the primary effector cells in liver fibrosis.In the normal liver,HSCs serve as the primary vitamin A storage cells in the body and retain a“quiescent”phenotype.However,after liver inj...Hepatic stellate cells(HSCs)are the primary effector cells in liver fibrosis.In the normal liver,HSCs serve as the primary vitamin A storage cells in the body and retain a“quiescent”phenotype.However,after liver injury,they transdifferentiate to an“activated”myofibroblast-like phenotype,which is associated with dramatic upregulation of smooth muscle specific actin and extracellular matrix proteins.The result is a fibrotic,stiff,and dysfunctional liver.Therefore,understanding the molecular mechanisms that govern HSC function is essential for the development of anti-fibrotic medications.The actin cytoskeleton has emerged as a key component of the fibrogenic response in wound healing.Recent data indicate that the cytoskeleton receives signals from the cellular microenvironment and translates them to cellular function—in particular,increased type I collagen expression.Dynamic in nature,the actin cytoskeleton continuously polymerizes and depolymerizes in response to changes in the cellular microenvironment.In this viewpoint,we discuss the recent developments underlying cytoskeletal actin dynamics in liver fibrosis,including how the cellular microenvironment affects HSC function and the molecular mechanisms that regulate the actininduced increase in collagen expression typical of activated HSCs.展开更多
Actin cytoskeleton undergoes rapid reorganization in response to internal and external cues. How the dynamics of actin cytoskeleton are regulated, and how its dynamics relate to its function are fundamental questions ...Actin cytoskeleton undergoes rapid reorganization in response to internal and external cues. How the dynamics of actin cytoskeleton are regulated, and how its dynamics relate to its function are fundamental questions in plant cell biology. The pollen tube is a well characterized actin-based cell morphogenesis in plants. One of the striking features of actin cytoskeleton characterized in the pollen tube is its surprisingly low level of actin polymer. This special phenomenon might relate to the function of actin cytoskeleton in pollen tubes. Understanding the molecular mechanism underlying this special phenomenon requires careful analysis of actin-binding proteins that modulate actin dynamics directly. Recent biochemical and biophysical analyses of several highly conserved plant actin-binding proteins reveal unusual and unexpected properties, which emphasizes the importance of carefully analyzing their action mechanism and cellular activity. In this review, we highlight an actin monomer sequestering protein, a barbed end capping protein and an F-actin severing and dynamizing protein in plant. We propose that these proteins function in harmony to regulate actin dynamics and maintain the low level of actin polymer in pollen tubes.展开更多
Free cytosolic Ca^2＋ （[Ca^2＋]cyt） is an ubiquitous second messenger in plant cell signaling, and [Ca^2＋]cyt elevation is associated with Ca^2＋-permeable channels in the plasma membrane and endomembranes regulate...Free cytosolic Ca^2＋ （[Ca^2＋]cyt） is an ubiquitous second messenger in plant cell signaling, and [Ca^2＋]cyt elevation is associated with Ca^2＋-permeable channels in the plasma membrane and endomembranes regulated by a wide range of stimuli. However, knowledge regarding Ca^2＋ channels and their regulation remains limited in planta. A type of voltage- dependent Ca^2＋-permeable channel was identified and characterized for the Vicia faba L. guard cell plasma membrane by using patch-clamp techniques. These channels are permeable to both Ba^2＋ and Ca^2＋, and their activities can be inhibited by micromolar Gd^3＋. The unitary conductance and the reversal potential of the channels depend on the Ca^2＋ or Ba^2＋ gradients across the plasma membrane. The inward whole-cell Ca^2＋ （Ba^2＋） current, as well as the unitary current amplitude and NPo of the single Ca^2＋ channel, increase along with the membrane hyperpolarization. Pharmacological experiments suggest that actin dynamics may serve as an upstream regulator of this type of calcium channel of the guard cell plasma membrane. Cytochalasin D, an actin polymerization blocker, activated the NPo of these channels at the single channel level and increased the current amplitude at the whole-cell level. But these channel activations and current increments could be restrained by pretreatment with an F-actin stabilizer, phalloidin. The potential physiological significance of this regulatory mechanism is also discussed.展开更多
Cells are capable of sensing and responding to the extracellular mechanical microenvironment via the actin skeleton.In vivo,tissues are frequently subject to mechanical forces,such as the rapid and significant shear f...Cells are capable of sensing and responding to the extracellular mechanical microenvironment via the actin skeleton.In vivo,tissues are frequently subject to mechanical forces,such as the rapid and significant shear flow encountered by vascular endothelial cells.However,the investigations about the transient response of intracellular actin networks under these intense external mechanical forces,their intrinsic mechanisms,and potential implications are very limited.Here,we observe that when cells are subject to the shear flow,an actin ring structure could be rapidly assembled at the periphery of the nucleus.To gain insights into the mechanism underlying this perinuclear actin ring assembly,we develop a computational model of actin dynamics.We demonstrate that this perinuclear actin ring assembly is triggered by the depolymerization of cortical actin,Arp2/3-dependent actin filament polymerization,and myosin-mediated actin network contraction.Furthermore,we discover that the compressive stress generated by the perinuclear actin ring could lead to a reduction in the nuclear spreading area,an increase in the nuclear height,and a decrease in the nuclear volume.The present model thus explains the mechanism of the perinuclear actin ring assembly under external mechanical forces and suggests that the spontaneous contraction of this actin structure can significantly impact nuclear morphology.展开更多
Actin cytoskeleton dynamics is critical for variety of cellular events including cell elongation, division and morphogenesis, and is tightly regulated by numerous groups of actin binding proteins. However it is not we...Actin cytoskeleton dynamics is critical for variety of cellular events including cell elongation, division and morphogenesis, and is tightly regulated by numerous groups of actin binding proteins. However it is not well understood how these actin binding proteins are modulated in a physiological condition by their interaction proteins. In this study, we describe that Arabidopsis 14-3-3 λ protein interacted with actin depolymerizing factor 1(ADF1) in plant to regulate F-actin stability and dynamics. Loss of 14-3-3 λin Arabidopsis resulted in longer etiolated hypocotyls in dark and changed actin cytoskeleton architecture in hypocotyl cells. Overexpression of ADF1 repressed 14-3-3 λ mutant hypocotyl elongation and actin dynamic phenotype. In addition, the phosphorylation level of ADF1 was increased and the subcellular localization of ADF1 was altered in 14-3-3 λ mutant. Consistent with these observations, the actin filaments were more stable in 14-3-3 λ mutant. Our results indicate that 14-3-3 λ protein mediates F-actin dynamics possibly through inhibiting ADF1 phosphorylation in vivo.展开更多
Polarized tip growth is a fundamental cellular process in many eukaryotes. In this study, we examined the dynamic restructuring of the actin cytoskeleton and its relationship to vesicle transport during pollen tip gro...Polarized tip growth is a fundamental cellular process in many eukaryotes. In this study, we examined the dynamic restructuring of the actin cytoskeleton and its relationship to vesicle transport during pollen tip growth in Arabidopsis. We found that actin filaments originating from the apical membrane form a specialized structure consisting of longitudinally aligned actin bundles at the cortex and inner cytoplasmic fila- ments with a distinct distribution. Using actin-based pharmacological treatments and genetic mutants in combination with FRAP （fluorescence recovery after photobleaching） technology to visualize the transport of vesicles within the growth domain of pollen tubes, we demonstrated that cortical actin filaments facilitate tip-ward vesicle transport. We also discovered that the inner apical actin filaments prevent backward movement of vesicles, thus ensuring that sufficient vesicles accumulate at the pollen tube tip to support the rapid growth of the pollen tube. The combinatorial effect of cortical and internal apical actin filaments perfectly explains the generation of the inverted ＂V＂ cone-shaped vesicle distribution pattern at the pollen tube tip. When pollen tubes turn, apical actin filaments at the facing side undergo depolymerization and repolymerization to reorient the apical actin structure toward the new growth direction. This actin restructuring precedes vesicle accumulation and changes in tube morphology. Thus, our study provides new insights into the functional relationship between actin dynamics and vesicle transport during rapid and directional pollen tube growth.展开更多
Cofilin is a pivotal actin-binding protein that plays a central role in regulating cytoskeletal dynamics,contributing to essential cellular processes such as migration,invasion,intracellular trafficking,and apoptosis....Cofilin is a pivotal actin-binding protein that plays a central role in regulating cytoskeletal dynamics,contributing to essential cellular processes such as migration,invasion,intracellular trafficking,and apoptosis.Dysregulation of cofilin is increasingly recognized to play a role in the pathogenesis and progression of various cancers,including gliomas and colorectal,breast,and bladder cancers.Cofilin facilitates cancer cell motility and metastasis by severing actin filaments,promoting invadopodia formation,and inducing epithelial-to-mesenchymal transition.Cofilin also modulates oncogenic signaling pathways,such as the phosphoinositide 3-kinase/protein kinase B and Rho guanosine triphosphatase pathways,and influences mitochondrial dynamics,thereby contributing to apoptosis resistance,metabolic reprogramming,and immune evasion.Recent advances in high-resolution imaging and multiomics analyses have revealed the spatiotemporal regulation of cofilin in the tumor microenvironment and its potential for use as a diagnostic and prognostic biomarker.Elevated cofilin expression is correlated with poor clinical outcomes and resistance to therapies,making cofilin an attractive target for cancer treatment.Preclinical models have demonstrated that targeting cofilin or its upstream regulators can improve therapeutic responses and suppress metastasis.This review explores the structural,functional,and regulatory roles of cofilin in cancer biology and highlights its emerging therapeutic potential.Future research should focus on the development of selective inhibitors and personalized treatment strategies to leverage cofilin as a target in precision oncology.展开更多
Background:Sepsis is a disease associated with high morbidity and mortality rates,especially among the elderly and patients in intensive care units.Disulfidptosis,a newly identified form of cell death triggered by dis...Background:Sepsis is a disease associated with high morbidity and mortality rates,especially among the elderly and patients in intensive care units.Disulfidptosis,a newly identified form of cell death triggered by disulfide stress,is emerging as a significant factor in disease progression.This study aimed to explore the diagnostic and prognostic value of disulfidptosis-related genes in sepsis.Methods:We obtained two datasets from the Gene Expression Omnibus(GEO)database to conduct our anal-ysis.Functional enrichment analysis was performed to identify relevant biological pathways.A protein-protein interaction network was constructed to identify hub genes critical to sepsis.Additionally,we analyzed the im-mune infiltration status in sepsis patients.The diagnostic value of these hub genes for sepsis was evaluated using nomograms,receiver operating characteristic(ROC)curves,and calibration curves in both training and valida-tion datasets.Finally,a miRNA-immune-related hub genes(miRNA-IHGs)regulatory network was developed to elucidate the synergistic interactions between miRNAs and their target genes.Results:A total of 3,469 differentially expressed genes(DEGs)were identified,of which seven were related to disulfidptosis(DR-DEGs).Functional enrichment analysis showed that DR-DEGs were significantly enriched in pathways related to actin dynamics.Five hub genes(MYH10,ACTN4,MYH9,FLNA,and IQGAP1)were identified as central to these processes.The analysis of immune infiltration revealed significantly lower levels of 11 immune cell types,while macrophages and regulatory T cells were significantly elevated in sepsis patients.The area under the ROC curves(AUCs)of the IHGs risk prediction model were 0.917 and 0.894 for the training and validation sets,respectively.A miRNA-IHGs regulatory network,comprising 17 nodes and 27 edges,was constructed,with MYH9 being the most frequently regulated by miRNAs.Conclusion:The pathophysiological process of sepsis appears to involve disulfidptosis,highlighting it as a potential new therapeutic targets for sepsis management.展开更多
基金This work was supported,in part,by the National Institute of Diabetes and Digestive and Kidney Disease(Grant No.P30 DK123704)the National Institute of General Medical Sciences(Grant No.P20 GM 130457).
文摘Hepatic stellate cells(HSCs)are the primary effector cells in liver fibrosis.In the normal liver,HSCs serve as the primary vitamin A storage cells in the body and retain a“quiescent”phenotype.However,after liver injury,they transdifferentiate to an“activated”myofibroblast-like phenotype,which is associated with dramatic upregulation of smooth muscle specific actin and extracellular matrix proteins.The result is a fibrotic,stiff,and dysfunctional liver.Therefore,understanding the molecular mechanisms that govern HSC function is essential for the development of anti-fibrotic medications.The actin cytoskeleton has emerged as a key component of the fibrogenic response in wound healing.Recent data indicate that the cytoskeleton receives signals from the cellular microenvironment and translates them to cellular function—in particular,increased type I collagen expression.Dynamic in nature,the actin cytoskeleton continuously polymerizes and depolymerizes in response to changes in the cellular microenvironment.In this viewpoint,we discuss the recent developments underlying cytoskeletal actin dynamics in liver fibrosis,including how the cellular microenvironment affects HSC function and the molecular mechanisms that regulate the actininduced increase in collagen expression typical of activated HSCs.
基金Supported by the Ministry of Science and Technology (2007CB947600)the National Natural Science Foundation of China (30771088 and30821007)the Chinese Academy of Sciences (Hundred talents program)
文摘Actin cytoskeleton undergoes rapid reorganization in response to internal and external cues. How the dynamics of actin cytoskeleton are regulated, and how its dynamics relate to its function are fundamental questions in plant cell biology. The pollen tube is a well characterized actin-based cell morphogenesis in plants. One of the striking features of actin cytoskeleton characterized in the pollen tube is its surprisingly low level of actin polymer. This special phenomenon might relate to the function of actin cytoskeleton in pollen tubes. Understanding the molecular mechanism underlying this special phenomenon requires careful analysis of actin-binding proteins that modulate actin dynamics directly. Recent biochemical and biophysical analyses of several highly conserved plant actin-binding proteins reveal unusual and unexpected properties, which emphasizes the importance of carefully analyzing their action mechanism and cellular activity. In this review, we highlight an actin monomer sequestering protein, a barbed end capping protein and an F-actin severing and dynamizing protein in plant. We propose that these proteins function in harmony to regulate actin dynamics and maintain the low level of actin polymer in pollen tubes.
基金Supported by the National Natural Science Foundation of China (30671029)the State Key Basic Research and Development Plan of China(2006CB100100)
文摘Free cytosolic Ca^2＋ （[Ca^2＋]cyt） is an ubiquitous second messenger in plant cell signaling, and [Ca^2＋]cyt elevation is associated with Ca^2＋-permeable channels in the plasma membrane and endomembranes regulated by a wide range of stimuli. However, knowledge regarding Ca^2＋ channels and their regulation remains limited in planta. A type of voltage- dependent Ca^2＋-permeable channel was identified and characterized for the Vicia faba L. guard cell plasma membrane by using patch-clamp techniques. These channels are permeable to both Ba^2＋ and Ca^2＋, and their activities can be inhibited by micromolar Gd^3＋. The unitary conductance and the reversal potential of the channels depend on the Ca^2＋ or Ba^2＋ gradients across the plasma membrane. The inward whole-cell Ca^2＋ （Ba^2＋） current, as well as the unitary current amplitude and NPo of the single Ca^2＋ channel, increase along with the membrane hyperpolarization. Pharmacological experiments suggest that actin dynamics may serve as an upstream regulator of this type of calcium channel of the guard cell plasma membrane. Cytochalasin D, an actin polymerization blocker, activated the NPo of these channels at the single channel level and increased the current amplitude at the whole-cell level. But these channel activations and current increments could be restrained by pretreatment with an F-actin stabilizer, phalloidin. The potential physiological significance of this regulatory mechanism is also discussed.
基金Project supported by the National Natural Science Foundation of China (Nos. 12025207 and 11872357)the Fundamental Research Funds for the Central Universities。
文摘Cells are capable of sensing and responding to the extracellular mechanical microenvironment via the actin skeleton.In vivo,tissues are frequently subject to mechanical forces,such as the rapid and significant shear flow encountered by vascular endothelial cells.However,the investigations about the transient response of intracellular actin networks under these intense external mechanical forces,their intrinsic mechanisms,and potential implications are very limited.Here,we observe that when cells are subject to the shear flow,an actin ring structure could be rapidly assembled at the periphery of the nucleus.To gain insights into the mechanism underlying this perinuclear actin ring assembly,we develop a computational model of actin dynamics.We demonstrate that this perinuclear actin ring assembly is triggered by the depolymerization of cortical actin,Arp2/3-dependent actin filament polymerization,and myosin-mediated actin network contraction.Furthermore,we discover that the compressive stress generated by the perinuclear actin ring could lead to a reduction in the nuclear spreading area,an increase in the nuclear height,and a decrease in the nuclear volume.The present model thus explains the mechanism of the perinuclear actin ring assembly under external mechanical forces and suggests that the spontaneous contraction of this actin structure can significantly impact nuclear morphology.
基金supported by the National Basic Research Program of China(2012CB114200)Foundation for Innovative Research Group of the National Natural Science Foundation of China(31421062)
文摘Actin cytoskeleton dynamics is critical for variety of cellular events including cell elongation, division and morphogenesis, and is tightly regulated by numerous groups of actin binding proteins. However it is not well understood how these actin binding proteins are modulated in a physiological condition by their interaction proteins. In this study, we describe that Arabidopsis 14-3-3 λ protein interacted with actin depolymerizing factor 1(ADF1) in plant to regulate F-actin stability and dynamics. Loss of 14-3-3 λin Arabidopsis resulted in longer etiolated hypocotyls in dark and changed actin cytoskeleton architecture in hypocotyl cells. Overexpression of ADF1 repressed 14-3-3 λ mutant hypocotyl elongation and actin dynamic phenotype. In addition, the phosphorylation level of ADF1 was increased and the subcellular localization of ADF1 was altered in 14-3-3 λ mutant. Consistent with these observations, the actin filaments were more stable in 14-3-3 λ mutant. Our results indicate that 14-3-3 λ protein mediates F-actin dynamics possibly through inhibiting ADF1 phosphorylation in vivo.
基金This work was supported by grants from the Ministry of Science and Technology of China （2013CB945100） and the National Natural Science Foundation of China （31671390 and 31471266）. X.Q. was supported by post-doctoral fellowships from Tsinghua-Peking Joint Center for Life Sciences and the China Postdoctoral Science Foundation （grant no. 2015M571028）.
文摘Polarized tip growth is a fundamental cellular process in many eukaryotes. In this study, we examined the dynamic restructuring of the actin cytoskeleton and its relationship to vesicle transport during pollen tip growth in Arabidopsis. We found that actin filaments originating from the apical membrane form a specialized structure consisting of longitudinally aligned actin bundles at the cortex and inner cytoplasmic fila- ments with a distinct distribution. Using actin-based pharmacological treatments and genetic mutants in combination with FRAP （fluorescence recovery after photobleaching） technology to visualize the transport of vesicles within the growth domain of pollen tubes, we demonstrated that cortical actin filaments facilitate tip-ward vesicle transport. We also discovered that the inner apical actin filaments prevent backward movement of vesicles, thus ensuring that sufficient vesicles accumulate at the pollen tube tip to support the rapid growth of the pollen tube. The combinatorial effect of cortical and internal apical actin filaments perfectly explains the generation of the inverted ＂V＂ cone-shaped vesicle distribution pattern at the pollen tube tip. When pollen tubes turn, apical actin filaments at the facing side undergo depolymerization and repolymerization to reorient the apical actin structure toward the new growth direction. This actin restructuring precedes vesicle accumulation and changes in tube morphology. Thus, our study provides new insights into the functional relationship between actin dynamics and vesicle transport during rapid and directional pollen tube growth.
文摘Cofilin is a pivotal actin-binding protein that plays a central role in regulating cytoskeletal dynamics,contributing to essential cellular processes such as migration,invasion,intracellular trafficking,and apoptosis.Dysregulation of cofilin is increasingly recognized to play a role in the pathogenesis and progression of various cancers,including gliomas and colorectal,breast,and bladder cancers.Cofilin facilitates cancer cell motility and metastasis by severing actin filaments,promoting invadopodia formation,and inducing epithelial-to-mesenchymal transition.Cofilin also modulates oncogenic signaling pathways,such as the phosphoinositide 3-kinase/protein kinase B and Rho guanosine triphosphatase pathways,and influences mitochondrial dynamics,thereby contributing to apoptosis resistance,metabolic reprogramming,and immune evasion.Recent advances in high-resolution imaging and multiomics analyses have revealed the spatiotemporal regulation of cofilin in the tumor microenvironment and its potential for use as a diagnostic and prognostic biomarker.Elevated cofilin expression is correlated with poor clinical outcomes and resistance to therapies,making cofilin an attractive target for cancer treatment.Preclinical models have demonstrated that targeting cofilin or its upstream regulators can improve therapeutic responses and suppress metastasis.This review explores the structural,functional,and regulatory roles of cofilin in cancer biology and highlights its emerging therapeutic potential.Future research should focus on the development of selective inhibitors and personalized treatment strategies to leverage cofilin as a target in precision oncology.
基金supported by the Clinical Research Project of Shandong University,2021(2021SDUCRCC004).
文摘Background:Sepsis is a disease associated with high morbidity and mortality rates,especially among the elderly and patients in intensive care units.Disulfidptosis,a newly identified form of cell death triggered by disulfide stress,is emerging as a significant factor in disease progression.This study aimed to explore the diagnostic and prognostic value of disulfidptosis-related genes in sepsis.Methods:We obtained two datasets from the Gene Expression Omnibus(GEO)database to conduct our anal-ysis.Functional enrichment analysis was performed to identify relevant biological pathways.A protein-protein interaction network was constructed to identify hub genes critical to sepsis.Additionally,we analyzed the im-mune infiltration status in sepsis patients.The diagnostic value of these hub genes for sepsis was evaluated using nomograms,receiver operating characteristic(ROC)curves,and calibration curves in both training and valida-tion datasets.Finally,a miRNA-immune-related hub genes(miRNA-IHGs)regulatory network was developed to elucidate the synergistic interactions between miRNAs and their target genes.Results:A total of 3,469 differentially expressed genes(DEGs)were identified,of which seven were related to disulfidptosis(DR-DEGs).Functional enrichment analysis showed that DR-DEGs were significantly enriched in pathways related to actin dynamics.Five hub genes(MYH10,ACTN4,MYH9,FLNA,and IQGAP1)were identified as central to these processes.The analysis of immune infiltration revealed significantly lower levels of 11 immune cell types,while macrophages and regulatory T cells were significantly elevated in sepsis patients.The area under the ROC curves(AUCs)of the IHGs risk prediction model were 0.917 and 0.894 for the training and validation sets,respectively.A miRNA-IHGs regulatory network,comprising 17 nodes and 27 edges,was constructed,with MYH9 being the most frequently regulated by miRNAs.Conclusion:The pathophysiological process of sepsis appears to involve disulfidptosis,highlighting it as a potential new therapeutic targets for sepsis management.
