Aim Endoplasmic reticulum (ER) stress is increasingly recognized as an important contributor to the pathophysiology of many diseases, and therapeutic interventions that target ER stress response emerge as new thera-...Aim Endoplasmic reticulum (ER) stress is increasingly recognized as an important contributor to the pathophysiology of many diseases, and therapeutic interventions that target ER stress response emerge as new thera- peutic modalities to treat cardiovascular diseases driven by prolonged ER stress. Ginkgolides K (GK) is a diterpene lactone constituent isolated from the leaves of Ginkgo biloba and has been found to possess potent neuroprotective properties. This study is aimed to investigate the cytoprotective effect of GK in cultured cardiomyocytes subjected to ER stress injury. Neonatal rat cardiomyocytes (NRCMs) were treated with ER stress inducer tunicamycin to mimic the ER stress injury. We demonstrated that GK pre-treatment mitigated ER stress-induced apoptosis in tunicamycin treated NRCMs. We observed that the activation of ER-associated degradation (ERAD) and autophagy were in- volved in the ER stress inhibition exerted by GK. These beneficial effects of GK were nearly abolished by the addi- tion of specific short interfering RNA (siRNA) for IRElα and XBP-1. Therefore, we conclude that GK might be a promising therapeutic agent for ER stress-mediated cardiovascular diseases, and ER-associated degradation (ERAD) and autophagy play a vital role in GK mediated cytoprotection.展开更多
OBJECTIVE Here we investigated the effects and the underlying mechanism of Ginkgolide K(1,10-dihydroxy-3,14-didehydroginkgolide,GK)on cardiac ER stress.METHODS Cell death,apoptosis,and ER stressrelated signalling path...OBJECTIVE Here we investigated the effects and the underlying mechanism of Ginkgolide K(1,10-dihydroxy-3,14-didehydroginkgolide,GK)on cardiac ER stress.METHODS Cell death,apoptosis,and ER stressrelated signalling pathwayswere measuredin cultured neonatal rat cardiomyocytes(NRCMs),treated with the ER stress inducers tunicamycin,hydrogen peroxide,and thapsigargin.Acute myocardial infarction was established using left coronary artery occlusion in mice,and infarct size was measured by triphenyltetrazolium chloride(TTC)staining.Echocardiography was used to assess heart function and transmission electron microscopy for evaluating ER expansion.RESULTS GK significantly decreased ER stress-induced cell death in both in vitro and in vivomodels.In ischemic injured mice,GK treatment reduced infarct size,rescued heart dysfunction and ameliorated ER dilation.Mechanistic studies revealed that the beneficial effects of GK occur through enhancement of inositol-requiring enzyme 1α(IRE1α)/X box-binding protein-1(XBP1)activity,which in turn leads to increased ER-associated degradation(ERAD)-mediated clearance of misfolded proteins and autophagy.In addition,GK is also able to partially repress the pro-apoptotic action of regulated IRE1-dependent decay(RIDD)and JNK pathway.CONCLUSION GK acts through selective activation of the IRE1α/XBP1 pathway to limit ER stress injury.GK is revealed as a promising therapeutic agent to ameliorate ER stress for treating cardiovascular diseases.展开更多
The endoplasmic reticulum,chloroplasts,and mitochondria are major plant organelles for protein synthesis,photosynthesis,metabolism,and energy production.Protein homeostasis in these organelles,maintained by a balance ...The endoplasmic reticulum,chloroplasts,and mitochondria are major plant organelles for protein synthesis,photosynthesis,metabolism,and energy production.Protein homeostasis in these organelles,maintained by a balance between protein synthesis and degradation,is essential for cell functions during plant growth,development,and stress resistance.Nucleus-encoded chloroplast-and mitochondrion-targeted proteins and ER-resident proteins are imported from the cytosol and undergo modification and maturation within their respective organelles.Protein folding is an error-prone process that is influenced by both developmental signals and environmental cues;a number of mechanisms have evolved to ensure efficient import and proper folding and maturation of proteins in plant organelles.Misfolded or damaged proteins with nonnative conformations are subject to degradation via complementary or competing pathways:intraorganelle proteases,the organelle-associated ubiquitin-proteasome system,and the selective autophagy of partial or entire organelles.When proteins in nonnative conformations accumulate,the organellespecific unfolded protein response operates to restore protein homeostasis by reducing protein folding demand,increasing protein folding capacity,and enhancing components involved in proteasome-associated protein degradation and autophagy.This review summarizes recent progress on the understanding of protein quality control in the ER,chloroplasts,and mitochondria in plants,with a focus on common mechanisms shared by these organelles during protein homeostasis.展开更多
STING is an endoplasmic reticulum(ER)-resident protein critical for sensing cytoplasmic DNA and promoting the production of type Ⅰ interferons;however,the role of STING in B cell receptor(BCR)signaling remains unclea...STING is an endoplasmic reticulum(ER)-resident protein critical for sensing cytoplasmic DNA and promoting the production of type Ⅰ interferons;however,the role of STING in B cell receptor(BCR)signaling remains unclear.We generated STING V154M knock-in mice and showed that B cells carrying constitutively activated STING specifically degraded membrane-bound IgM,Ig a and Igβ via SEL1L/HRD1-mediated ER-associated degradation(ERAD).B cells with activated STING were thus less capable of responding to BCR activation by phosphorylating Igα and Syk than those without activated STING.When immunized with T-independent antigens,STING V154M mice produced significantly fewer antigen-specific plasma cells and antibodies than immunized wild-type(WT)mice.We further generated B cell-specific STING^(KO) mice and showed that STING^(KO) B cells indeed responded to activation by transducing stronger BCR signals than their STING-proficient counterparts.When B cell-specific STING^(KO) mice were T-independently immunized,they produced significantly more antigen-specific plasma cells and antibodies than immunized STIN^(WT)mice.Since both human and m ouse IGHV-unmutated malignant chronic lymphocytic leukemia(CLL)cells downregulated the expression of STING,we explored whether STING downregulation could contribute to the well-established robust BCR signaling phenotype in malignant CLL cells.We generated a STING-deficient CLL mouse model and showed that STING-deficient CLL cells were indeed more responsive to BCR activation than their STING-proficient counterparts.These results revealed a novel B cell-intrinsic role of STING in negatively regulating BCR signaling in both normal and malignant B cells.展开更多
文摘Aim Endoplasmic reticulum (ER) stress is increasingly recognized as an important contributor to the pathophysiology of many diseases, and therapeutic interventions that target ER stress response emerge as new thera- peutic modalities to treat cardiovascular diseases driven by prolonged ER stress. Ginkgolides K (GK) is a diterpene lactone constituent isolated from the leaves of Ginkgo biloba and has been found to possess potent neuroprotective properties. This study is aimed to investigate the cytoprotective effect of GK in cultured cardiomyocytes subjected to ER stress injury. Neonatal rat cardiomyocytes (NRCMs) were treated with ER stress inducer tunicamycin to mimic the ER stress injury. We demonstrated that GK pre-treatment mitigated ER stress-induced apoptosis in tunicamycin treated NRCMs. We observed that the activation of ER-associated degradation (ERAD) and autophagy were in- volved in the ER stress inhibition exerted by GK. These beneficial effects of GK were nearly abolished by the addi- tion of specific short interfering RNA (siRNA) for IRElα and XBP-1. Therefore, we conclude that GK might be a promising therapeutic agent for ER stress-mediated cardiovascular diseases, and ER-associated degradation (ERAD) and autophagy play a vital role in GK mediated cytoprotection.
文摘OBJECTIVE Here we investigated the effects and the underlying mechanism of Ginkgolide K(1,10-dihydroxy-3,14-didehydroginkgolide,GK)on cardiac ER stress.METHODS Cell death,apoptosis,and ER stressrelated signalling pathwayswere measuredin cultured neonatal rat cardiomyocytes(NRCMs),treated with the ER stress inducers tunicamycin,hydrogen peroxide,and thapsigargin.Acute myocardial infarction was established using left coronary artery occlusion in mice,and infarct size was measured by triphenyltetrazolium chloride(TTC)staining.Echocardiography was used to assess heart function and transmission electron microscopy for evaluating ER expansion.RESULTS GK significantly decreased ER stress-induced cell death in both in vitro and in vivomodels.In ischemic injured mice,GK treatment reduced infarct size,rescued heart dysfunction and ameliorated ER dilation.Mechanistic studies revealed that the beneficial effects of GK occur through enhancement of inositol-requiring enzyme 1α(IRE1α)/X box-binding protein-1(XBP1)activity,which in turn leads to increased ER-associated degradation(ERAD)-mediated clearance of misfolded proteins and autophagy.In addition,GK is also able to partially repress the pro-apoptotic action of regulated IRE1-dependent decay(RIDD)and JNK pathway.CONCLUSION GK acts through selective activation of the IRE1α/XBP1 pathway to limit ER stress injury.GK is revealed as a promising therapeutic agent to ameliorate ER stress for treating cardiovascular diseases.
基金Projects associated with protein homeostasis in the Liu Lab are financially supported by grants from the National Natural Science Foundation of China(31625004,31872653,and 31800210)the Zhejiang Provincial Talent Program(2019R52005)the 111 Project(B14027).
文摘The endoplasmic reticulum,chloroplasts,and mitochondria are major plant organelles for protein synthesis,photosynthesis,metabolism,and energy production.Protein homeostasis in these organelles,maintained by a balance between protein synthesis and degradation,is essential for cell functions during plant growth,development,and stress resistance.Nucleus-encoded chloroplast-and mitochondrion-targeted proteins and ER-resident proteins are imported from the cytosol and undergo modification and maturation within their respective organelles.Protein folding is an error-prone process that is influenced by both developmental signals and environmental cues;a number of mechanisms have evolved to ensure efficient import and proper folding and maturation of proteins in plant organelles.Misfolded or damaged proteins with nonnative conformations are subject to degradation via complementary or competing pathways:intraorganelle proteases,the organelle-associated ubiquitin-proteasome system,and the selective autophagy of partial or entire organelles.When proteins in nonnative conformations accumulate,the organellespecific unfolded protein response operates to restore protein homeostasis by reducing protein folding demand,increasing protein folding capacity,and enhancing components involved in proteasome-associated protein degradation and autophagy.This review summarizes recent progress on the understanding of protein quality control in the ER,chloroplasts,and mitochondria in plants,with a focus on common mechanisms shared by these organelles during protein homeostasis.
基金supported by grants(R01CA163910 and R01CA190860)from the NIH/NCI.
文摘STING is an endoplasmic reticulum(ER)-resident protein critical for sensing cytoplasmic DNA and promoting the production of type Ⅰ interferons;however,the role of STING in B cell receptor(BCR)signaling remains unclear.We generated STING V154M knock-in mice and showed that B cells carrying constitutively activated STING specifically degraded membrane-bound IgM,Ig a and Igβ via SEL1L/HRD1-mediated ER-associated degradation(ERAD).B cells with activated STING were thus less capable of responding to BCR activation by phosphorylating Igα and Syk than those without activated STING.When immunized with T-independent antigens,STING V154M mice produced significantly fewer antigen-specific plasma cells and antibodies than immunized wild-type(WT)mice.We further generated B cell-specific STING^(KO) mice and showed that STING^(KO) B cells indeed responded to activation by transducing stronger BCR signals than their STING-proficient counterparts.When B cell-specific STING^(KO) mice were T-independently immunized,they produced significantly more antigen-specific plasma cells and antibodies than immunized STIN^(WT)mice.Since both human and m ouse IGHV-unmutated malignant chronic lymphocytic leukemia(CLL)cells downregulated the expression of STING,we explored whether STING downregulation could contribute to the well-established robust BCR signaling phenotype in malignant CLL cells.We generated a STING-deficient CLL mouse model and showed that STING-deficient CLL cells were indeed more responsive to BCR activation than their STING-proficient counterparts.These results revealed a novel B cell-intrinsic role of STING in negatively regulating BCR signaling in both normal and malignant B cells.