Macroautophagy is a multistep, vacuolar, degradation pathway terminating in the lysosomal compartment, and it is of fundamental importance in tissue homeostasis. In this review, we consider macroautophagy in the light...Macroautophagy is a multistep, vacuolar, degradation pathway terminating in the lysosomal compartment, and it is of fundamental importance in tissue homeostasis. In this review, we consider macroautophagy in the light of recent advances in our understanding of the formation of autophagosomes, which are double-membrane-bound vacuoles that sequester cytoplasmic cargos and deliver them to lysosomes. In most cases, this final step is preceded by a maturation step during which autophagosomes interact with the endocytic pathway. The discovery of AuTophaGyrelated genes has greatly increased our knowledge about the mechanism responsible for antophagosome formation, and there has also been progress in the understanding of molecular aspects of autophagosome maturation. Finally, the regulation of autophagy is now better understood because of the discovery that the activity of Atg complexes is targeted by protein kinases, and owing to the importance of nuclear regulation via transcription factors in regulating the expression of autophagy genes.展开更多
To accommodate two seemingly contradictory biological roles in plant physiology, providing both the rigid structural support of plant cells and the adjustable elasticity needed for cell expansion, the composition of t...To accommodate two seemingly contradictory biological roles in plant physiology, providing both the rigid structural support of plant cells and the adjustable elasticity needed for cell expansion, the composition of the plant cell wall has evolved to become an intricate network of cellulosic, hemicellulosic, and pectic polysaccharides and protein. Due to its complexity, many aspects of the cell wall influence plant cell expansion, and many new and insightful observations and technologies are forthcoming. The biosynthesis of cell wall polymers and the roles of the variety of proteins involved in polysaccharide synthesis continue to be characterized. The interactions within the cell wall polymer network and the modification of these interactions provide insight into how the plant cell wall provides its dual function. The complex cell wall architecture is controlled and organized in part by the dynamic intracellular cytoskeleton and by diverse trafficking pathways of the cell wall polymers and cell wall-related machinery. Meanwhile, the cell wall is continually influenced by hormonal and integrity sensing stimuli that are perceived by the cell. These many processes cooperate to construct, maintain, and manipulate the intricate plant cell wall--an essential structure for the sustaining of the plant stature, growth, and life.展开更多
Root hairs and pollen tubes are formed through tip growth, a process requiring synthesis of new cell wall material and the precise targeting and integration of these components to a selected apical plasma membrane dom...Root hairs and pollen tubes are formed through tip growth, a process requiring synthesis of new cell wall material and the precise targeting and integration of these components to a selected apical plasma membrane domain in the growing tips of these cells. Presence of a tip-focused calcium gradient, control of actin cytoskeleton dynamics, and formation and targeting of secretory vesicles are essential to tip growth. Similar to cells undergoing diffuse growth, cellulose, hemi-celluloses, and pectins are also deposited in the growing apices of tip-growing cells. However, differences in the manner in which these cell wall components are targeted and inserted in the expanding portion of tip-growing cells is reflected by the identification of elements of the plant cell wall synthesis machinery which have been shown to play unique roles in tip-growing cells. In this review, we summarize our current understanding of the tip growth process, with a particular focus on the subcellular targeting of newly synthesized cell wall components, and their roles in this form of plant cell expansion.展开更多
The cell wall, a crucial cell compartment, is composed of a network of polysaccharides and proteins, providing structural support and protection from external stimuli.
Pten controls a signaling axis that is implicated to regulate cell proliferation,growth,survival,migration,and metabolism.The molecular mechanisms underlying the specificity of Pten responses to such diverse cellular ...Pten controls a signaling axis that is implicated to regulate cell proliferation,growth,survival,migration,and metabolism.The molecular mechanisms underlying the specificity of Pten responses to such diverse cellular functions are currently poorly understood.Herewe report the control of Pten activity and signaling specificity during the cell cycle by Ndfip1 regulation of Pten spatial distribution.Genetic deletion of Ndfip1 resulted in a loss of Pten nuclear compartmentalization and increased cell proliferation,despite cytoplasmic Pten remaining active in regulating PI3K/Akt signaling.Cells lacking nuclear Pten were found to have dysregulated levels of Plk1 and cyclin D1 that could drive cell proliferation.In vivo,transgene expression of Ndfip1 in the developing brain increased nuclear Pten and lengthened the cell cycle of neuronal progenitors,resulting in microencephaly.Our results show that local partitioning of Pten from the cytoplasm to the nucleus represents a key mechanism contributing to the specificity of Pten signaling during cell proliferation.展开更多
Much research has focused on the PI3-kinase and PTEN signaling pathway with the aim to stimulate repair of the injured central nervous system.Axons in the central nervous system fail to regenerate,meaning that injurie...Much research has focused on the PI3-kinase and PTEN signaling pathway with the aim to stimulate repair of the injured central nervous system.Axons in the central nervous system fail to regenerate,meaning that injuries or diseases that cause loss of axonal connectivity have life-changing consequences.In 2008,genetic deletion of PTEN was identified as a means of stimulating robust regeneration in the optic nerve.PTEN is a phosphatase that opposes the actions of PI3-kinase,a family of enzymes that function to generate the membrane phospholipid PIP_(3) from PIP_(2)(phosphatidylinositol(3,4,5)-trisphosphate from phosphatidylinositol(4,5)-bisphosphate).Deletion of PTEN therefore allows elevated signaling downstream of PI3-kinase,and was initially demonstrated to promote axon regeneration by signaling through mTOR.More recently,additional mechanisms have been identified that contribute to the neuron-intrinsic control of regenerative ability.This review describes neuronal signaling pathways downstream of PI3-kinase and PIP3,and considers them in relation to both developmental and regenerative axon growth.We briefly discuss the key neuron-intrinsic mechanisms that govern regenerative ability,and describe how these are affected by signaling through PI3-kinase.We highlight the recent finding of a developmental decline in the generation of PIP_(3) as a key reason for regenerative failure,and summarize the studies that target an increase in signaling downstream of PI3-kinase to facilitate regeneration in the adult central nervous system.Finally,we discuss obstacles that remain to be overcome in order to generate a robust strategy for repairing the injured central nervous system through manipulation of PI3-kinase signaling.展开更多
The sub-cellular events that occur during the ethylene-modulated cell elongation were characterized by examining the ultra-structure of etiolated Arabidopsis seedling hypocotyl cells. Preventing the basal level ethyle...The sub-cellular events that occur during the ethylene-modulated cell elongation were characterized by examining the ultra-structure of etiolated Arabidopsis seedling hypocotyl cells. Preventing the basal level ethylene response facilitated cell elongation, and the cells exhibited wall loosening and separation phenotype. Nearby the wall separation sites were frequently associated with an increase in the cortical rough endoplasmic reticulum （rER） membranes, the presence of paramural bodies, and the circular Golgi formation. The cortical rER proliferation and circular Golgi phenotype were reverted by the protein biosynthesis inhibitor cycloheximide. The cortical rER membranes were longer when the ethylene response was prevented and shortened with elevated ethylene responses. Proteomic changes between wild type and the ethylene-insensitive mutant ethylene insensitive2 （ein2） seedling hypocotyls indicated that distinct subsets of proteins involving endomembrane trafficking, remodeling, and wall modifications were differentially expressed. FM4-64 staining supported the proteomic changes, which indicated reduced endocytosis activity with alleviation of the ethylene response. The basal level ethylene response has an important role in endomembrane trafficking, biological materials transport and maintenance of the endomembrane organization. It is possible that endomembrane alterations may partly associate with the wall modifications, though the biological significance of the alterations should be addressed in future studies.展开更多
Semaphorins were originally identified as axon guidance factors involved in the development of the neuronal system. However, accumulating evidence indicates that several members of semaphorins, so-called ＇immune sema...Semaphorins were originally identified as axon guidance factors involved in the development of the neuronal system. However, accumulating evidence indicates that several members of semaphorins, so-called ＇immune semaphorins＇, are crucially involved in various phases of immune responses. These semaphorins regulate both immune cell interactions and immune cell trafficking during physiological and pathological immune responses. Here, we review the following two functional aspects of semaphorins and their receptors in immune responses： their functions in cell-cell interactions and their involvement in immune cell trafficking.展开更多
Plants have evolved a sophisticated immune system to fight against pathogenic microbes. Upon detection of pathogen invasion by immune receptors, the immune system is turned on, resulting in production of antimicrobial...Plants have evolved a sophisticated immune system to fight against pathogenic microbes. Upon detection of pathogen invasion by immune receptors, the immune system is turned on, resulting in production of antimicrobial molecules including pathogenesis-related（PR） proteins.Conceivably, an efficient immune response depends on the capacity of the plant cell＇s protein/membrane trafficking network to deploy the right defense-associated molecules in the right place at the right time. Recent research in this area shows that while the abundance of cell surface immune receptors is regulated by endocytosis, many intracellular immune receptors, when activated, are partitioned between the cytoplasm and the nucleus for induction of defense genes and activation of programmed cell death, respectively. Vesicle transport is an essential process for secretion of PR proteins to the apoplastic space and targeting of defense-related proteins to the plasma membrane or other endomembrane compartments. In this review, we discuss the various aspects of protein trafficking during plant immunity, with a focus on the immunity proteins on the move and the major components of the trafficking machineries engaged.展开更多
The discovery of CAR T cell immunotherapy, also known as chimeric antigen receptor (CAR) T cell immunotherapy, has added a new dimension to the world of cancer treatment. This is a gene-based treatment in which T cell...The discovery of CAR T cell immunotherapy, also known as chimeric antigen receptor (CAR) T cell immunotherapy, has added a new dimension to the world of cancer treatment. This is a gene-based treatment in which T cells from the patient’s body are taken and genetically engineered in the lab to grow receptors. T cells containing this receptor are then injected into the patient’s body to bind to the antigen on the surface area of the cancer cell and kill the cancer cell. Structurally, the co-stimulatory domain added to CAR T cells has now reached the 5<sup>th</sup> GEN of chimeric antigen receptor T cells. Chimeric antigen T cell immunotherapy is the first FDA-approved treatment for hematological malignancies that is both safe and effective. However, due to some challenges such as a lack of safety control, an immunosuppressive tumor microenvironment, ineffective T cell trafficking, and so on, CAR-T immunotherapy treatment for solid malignancy is still in the clinical phase. In the result and discussion, we have presented a survey of CAR T cell therapy with a combination of pharmacological drugs. The things we mentioned are that CAR T cell immunotherapy is innovative, suitable, elegant, and also controls synergistic anti-cancer effects. A better understanding of combinatory CAR T cell therapies provides fundamental information for improvement of those therapies, in addition to the article highlighting future opportunities, commercial advancements, and various applications of CAR T cell therapy in different cancer cells. In the entire review article, we have highlighted the neck and crop of CAR T cell therapy, from which it is easy to understand the therapy and the need for this therapy in cancer prevention and its progress.展开更多
Previously, we established a model in which physiologically adequate function of the autologous β cells was recovered in non-obese diabetic （NOD） mice after the onset of hyperglycemia by rendering them hemopoietic ...Previously, we established a model in which physiologically adequate function of the autologous β cells was recovered in non-obese diabetic （NOD） mice after the onset of hyperglycemia by rendering them hemopoietic chimera. These mice were termed antea-diabetic. In the current study, we addressed the role of T regulatory （Treg） cells in the mechanisms mediating the restoration of euglycemia in the antea-diabetic NOD model. The data generated in this study demonstrated that the numbers of Treg cells were decreased in unmanipulated NOD mice, with the most profound deficiency detected in the pancreatic lymph nodes （PLNs）. The impaired retention of the Treg cells in the PLNs correlated with the locally compromised profile of the chemokines involved in their trafficking, with the most prominent decrease observed in SDF-1. The amelioration of autoimmunity and restoration of euglycemia observed in the antea-diabetic mice was associated with restoration of the Treg cell population in the PLNs. These data indicate that the function of the SDF-1/CXCR4 axis and the retention of Treg cells in the PLNs have a potential role in diabetogenesis and in the amelioration of autoimmunity and β cell regeneration in the antea-diabetic model. We have demonstrated in the antea-diabetic mouse model that lifelong recovery of the β cells has a strong correlation with normalization of the Treg cell population in the PLNs. This finding offers new opportunities for testing the immunomodulatory regimens that promote accumulation of Treg cells in the PLNs as a therapeutic approach for type 1 diabetes （TID）.展开更多
文摘Macroautophagy is a multistep, vacuolar, degradation pathway terminating in the lysosomal compartment, and it is of fundamental importance in tissue homeostasis. In this review, we consider macroautophagy in the light of recent advances in our understanding of the formation of autophagosomes, which are double-membrane-bound vacuoles that sequester cytoplasmic cargos and deliver them to lysosomes. In most cases, this final step is preceded by a maturation step during which autophagosomes interact with the endocytic pathway. The discovery of AuTophaGyrelated genes has greatly increased our knowledge about the mechanism responsible for antophagosome formation, and there has also been progress in the understanding of molecular aspects of autophagosome maturation. Finally, the regulation of autophagy is now better understood because of the discovery that the activity of Atg complexes is targeted by protein kinases, and owing to the importance of nuclear regulation via transcription factors in regulating the expression of autophagy genes.
文摘To accommodate two seemingly contradictory biological roles in plant physiology, providing both the rigid structural support of plant cells and the adjustable elasticity needed for cell expansion, the composition of the plant cell wall has evolved to become an intricate network of cellulosic, hemicellulosic, and pectic polysaccharides and protein. Due to its complexity, many aspects of the cell wall influence plant cell expansion, and many new and insightful observations and technologies are forthcoming. The biosynthesis of cell wall polymers and the roles of the variety of proteins involved in polysaccharide synthesis continue to be characterized. The interactions within the cell wall polymer network and the modification of these interactions provide insight into how the plant cell wall provides its dual function. The complex cell wall architecture is controlled and organized in part by the dynamic intracellular cytoskeleton and by diverse trafficking pathways of the cell wall polymers and cell wall-related machinery. Meanwhile, the cell wall is continually influenced by hormonal and integrity sensing stimuli that are perceived by the cell. These many processes cooperate to construct, maintain, and manipulate the intricate plant cell wall--an essential structure for the sustaining of the plant stature, growth, and life.
基金funded by the Division of Chemical Sciences, Geosciences, and Biosciences, Offce of Basic Energy Sciences of the U.S. Department of Energy through Grant DE‐FG02‐07ER15887funds from the National Science Foundation grant 0937323 provided salary support for F.G
文摘Root hairs and pollen tubes are formed through tip growth, a process requiring synthesis of new cell wall material and the precise targeting and integration of these components to a selected apical plasma membrane domain in the growing tips of these cells. Presence of a tip-focused calcium gradient, control of actin cytoskeleton dynamics, and formation and targeting of secretory vesicles are essential to tip growth. Similar to cells undergoing diffuse growth, cellulose, hemi-celluloses, and pectins are also deposited in the growing apices of tip-growing cells. However, differences in the manner in which these cell wall components are targeted and inserted in the expanding portion of tip-growing cells is reflected by the identification of elements of the plant cell wall synthesis machinery which have been shown to play unique roles in tip-growing cells. In this review, we summarize our current understanding of the tip growth process, with a particular focus on the subcellular targeting of newly synthesized cell wall components, and their roles in this form of plant cell expansion.
基金supported by UC Davis start up fundsa Hellman fellowship to G.D. N.W. was supported by a Plant Sciences GSR and the CREATE-IGERT NSF DGE-0653984 grant
文摘The cell wall, a crucial cell compartment, is composed of a network of polysaccharides and proteins, providing structural support and protection from external stimuli.
基金This work was supported by the Australia National Health and Medical Research Council through Program and Project Grants(grant numbers 569575 and 1066895)the Victorian Government through the Operational Infrastructure Scheme.
文摘Pten controls a signaling axis that is implicated to regulate cell proliferation,growth,survival,migration,and metabolism.The molecular mechanisms underlying the specificity of Pten responses to such diverse cellular functions are currently poorly understood.Herewe report the control of Pten activity and signaling specificity during the cell cycle by Ndfip1 regulation of Pten spatial distribution.Genetic deletion of Ndfip1 resulted in a loss of Pten nuclear compartmentalization and increased cell proliferation,despite cytoplasmic Pten remaining active in regulating PI3K/Akt signaling.Cells lacking nuclear Pten were found to have dysregulated levels of Plk1 and cyclin D1 that could drive cell proliferation.In vivo,transgene expression of Ndfip1 in the developing brain increased nuclear Pten and lengthened the cell cycle of neuronal progenitors,resulting in microencephaly.Our results show that local partitioning of Pten from the cytoplasm to the nucleus represents a key mechanism contributing to the specificity of Pten signaling during cell proliferation.
基金the Medical Research Council(MR/R004544/1,MR/R004463/1,to RE)EU ERA-NET NEURON(AxonRepair grant,to BN)+1 种基金Fight for Sight(5119/5120,and 5065-5066,to RE)National Eye Research Centre(to RE).
文摘Much research has focused on the PI3-kinase and PTEN signaling pathway with the aim to stimulate repair of the injured central nervous system.Axons in the central nervous system fail to regenerate,meaning that injuries or diseases that cause loss of axonal connectivity have life-changing consequences.In 2008,genetic deletion of PTEN was identified as a means of stimulating robust regeneration in the optic nerve.PTEN is a phosphatase that opposes the actions of PI3-kinase,a family of enzymes that function to generate the membrane phospholipid PIP_(3) from PIP_(2)(phosphatidylinositol(3,4,5)-trisphosphate from phosphatidylinositol(4,5)-bisphosphate).Deletion of PTEN therefore allows elevated signaling downstream of PI3-kinase,and was initially demonstrated to promote axon regeneration by signaling through mTOR.More recently,additional mechanisms have been identified that contribute to the neuron-intrinsic control of regenerative ability.This review describes neuronal signaling pathways downstream of PI3-kinase and PIP3,and considers them in relation to both developmental and regenerative axon growth.We briefly discuss the key neuron-intrinsic mechanisms that govern regenerative ability,and describe how these are affected by signaling through PI3-kinase.We highlight the recent finding of a developmental decline in the generation of PIP_(3) as a key reason for regenerative failure,and summarize the studies that target an increase in signaling downstream of PI3-kinase to facilitate regeneration in the adult central nervous system.Finally,we discuss obstacles that remain to be overcome in order to generate a robust strategy for repairing the injured central nervous system through manipulation of PI3-kinase signaling.
基金supported by the National Natural Sciences Foundation of China (31070249, 31100212, and 31123006)the Chinese Ministry of Science and Technology (2011CB100700 and 2012AA10A302-2)the Chinese Academy of Sciences (KSCX2-EW-J-12)
文摘The sub-cellular events that occur during the ethylene-modulated cell elongation were characterized by examining the ultra-structure of etiolated Arabidopsis seedling hypocotyl cells. Preventing the basal level ethylene response facilitated cell elongation, and the cells exhibited wall loosening and separation phenotype. Nearby the wall separation sites were frequently associated with an increase in the cortical rough endoplasmic reticulum （rER） membranes, the presence of paramural bodies, and the circular Golgi formation. The cortical rER proliferation and circular Golgi phenotype were reverted by the protein biosynthesis inhibitor cycloheximide. The cortical rER membranes were longer when the ethylene response was prevented and shortened with elevated ethylene responses. Proteomic changes between wild type and the ethylene-insensitive mutant ethylene insensitive2 （ein2） seedling hypocotyls indicated that distinct subsets of proteins involving endomembrane trafficking, remodeling, and wall modifications were differentially expressed. FM4-64 staining supported the proteomic changes, which indicated reduced endocytosis activity with alleviation of the ethylene response. The basal level ethylene response has an important role in endomembrane trafficking, biological materials transport and maintenance of the endomembrane organization. It is possible that endomembrane alterations may partly associate with the wall modifications, though the biological significance of the alterations should be addressed in future studies.
文摘Semaphorins were originally identified as axon guidance factors involved in the development of the neuronal system. However, accumulating evidence indicates that several members of semaphorins, so-called ＇immune semaphorins＇, are crucially involved in various phases of immune responses. These semaphorins regulate both immune cell interactions and immune cell trafficking during physiological and pathological immune responses. Here, we review the following two functional aspects of semaphorins and their receptors in immune responses： their functions in cell-cell interactions and their involvement in immune cell trafficking.
基金supported by the Major Research Plan from the Ministry of Science and Technology of China(No.2016YFA0100600,2015CB964400,2011CB964800,2013CB966902)the National Natural Science Foundation of China(No.81421002,81430004,81330015,91519315)
基金supported by a grant from the National Science Foundation(grant number IOS-1146589)to S.X.Research in the Wang lab is supported by grants from the National Natural Science Foundation of China(grant numbers 31371931 and 31430072)to W.M.W
文摘Plants have evolved a sophisticated immune system to fight against pathogenic microbes. Upon detection of pathogen invasion by immune receptors, the immune system is turned on, resulting in production of antimicrobial molecules including pathogenesis-related（PR） proteins.Conceivably, an efficient immune response depends on the capacity of the plant cell＇s protein/membrane trafficking network to deploy the right defense-associated molecules in the right place at the right time. Recent research in this area shows that while the abundance of cell surface immune receptors is regulated by endocytosis, many intracellular immune receptors, when activated, are partitioned between the cytoplasm and the nucleus for induction of defense genes and activation of programmed cell death, respectively. Vesicle transport is an essential process for secretion of PR proteins to the apoplastic space and targeting of defense-related proteins to the plasma membrane or other endomembrane compartments. In this review, we discuss the various aspects of protein trafficking during plant immunity, with a focus on the immunity proteins on the move and the major components of the trafficking machineries engaged.
文摘The discovery of CAR T cell immunotherapy, also known as chimeric antigen receptor (CAR) T cell immunotherapy, has added a new dimension to the world of cancer treatment. This is a gene-based treatment in which T cells from the patient’s body are taken and genetically engineered in the lab to grow receptors. T cells containing this receptor are then injected into the patient’s body to bind to the antigen on the surface area of the cancer cell and kill the cancer cell. Structurally, the co-stimulatory domain added to CAR T cells has now reached the 5<sup>th</sup> GEN of chimeric antigen receptor T cells. Chimeric antigen T cell immunotherapy is the first FDA-approved treatment for hematological malignancies that is both safe and effective. However, due to some challenges such as a lack of safety control, an immunosuppressive tumor microenvironment, ineffective T cell trafficking, and so on, CAR-T immunotherapy treatment for solid malignancy is still in the clinical phase. In the result and discussion, we have presented a survey of CAR T cell therapy with a combination of pharmacological drugs. The things we mentioned are that CAR T cell immunotherapy is innovative, suitable, elegant, and also controls synergistic anti-cancer effects. A better understanding of combinatory CAR T cell therapies provides fundamental information for improvement of those therapies, in addition to the article highlighting future opportunities, commercial advancements, and various applications of CAR T cell therapy in different cancer cells. In the entire review article, we have highlighted the neck and crop of CAR T cell therapy, from which it is easy to understand the therapy and the need for this therapy in cancer prevention and its progress.
文摘Previously, we established a model in which physiologically adequate function of the autologous β cells was recovered in non-obese diabetic （NOD） mice after the onset of hyperglycemia by rendering them hemopoietic chimera. These mice were termed antea-diabetic. In the current study, we addressed the role of T regulatory （Treg） cells in the mechanisms mediating the restoration of euglycemia in the antea-diabetic NOD model. The data generated in this study demonstrated that the numbers of Treg cells were decreased in unmanipulated NOD mice, with the most profound deficiency detected in the pancreatic lymph nodes （PLNs）. The impaired retention of the Treg cells in the PLNs correlated with the locally compromised profile of the chemokines involved in their trafficking, with the most prominent decrease observed in SDF-1. The amelioration of autoimmunity and restoration of euglycemia observed in the antea-diabetic mice was associated with restoration of the Treg cell population in the PLNs. These data indicate that the function of the SDF-1/CXCR4 axis and the retention of Treg cells in the PLNs have a potential role in diabetogenesis and in the amelioration of autoimmunity and β cell regeneration in the antea-diabetic model. We have demonstrated in the antea-diabetic mouse model that lifelong recovery of the β cells has a strong correlation with normalization of the Treg cell population in the PLNs. This finding offers new opportunities for testing the immunomodulatory regimens that promote accumulation of Treg cells in the PLNs as a therapeutic approach for type 1 diabetes （TID）.
