VP22是一种保守的被膜蛋白,广泛存在于伪狂犬病病毒(PRV)和HSV-1等α-疱疹病毒中。HSV-1的VP22是病毒的重要毒力因子,它通过调节病毒蛋白和宿主蛋白的亚细胞定位,增强病毒的神经毒性;HSV-1 VP22还能够抑制AIM2炎症小体的激活,进而促进...VP22是一种保守的被膜蛋白,广泛存在于伪狂犬病病毒(PRV)和HSV-1等α-疱疹病毒中。HSV-1的VP22是病毒的重要毒力因子,它通过调节病毒蛋白和宿主蛋白的亚细胞定位,增强病毒的神经毒性;HSV-1 VP22还能够抑制AIM2炎症小体的激活,进而促进病毒的复制。然而,PRV VP22与HSV-1 VP22的同源性仅为26%,其在病毒感染和致病中的作用尚不明确。近期,mBio杂志发表了题为“Suppression of ZBP1-mediated NLRP3 inflammasome by the tegument protein VP22 facilitates pseudorabies virus infection”的研究论文,论文的通讯作者为南京农业大学动物医学院姜平教授和刘星教授,第一作者为博士后马梓承。本研究揭示了ZBP1介导的NLRP3炎症小体在PRV感染中的作用,并发现PRV VP22通过抑制该途径介导的炎症反应,促进病毒的复制和致病性。该研究成果为理解PRV复制和致病机制提供了新的视角。展开更多
Z-DNA binding protein 1(ZBP1)has emerged as a critical player in cancer biology,functioning as a cytosolic nucleic acid sensor that triggers PANoptosis,a form of programmed cell death that integrates pyroptosis,apopto...Z-DNA binding protein 1(ZBP1)has emerged as a critical player in cancer biology,functioning as a cytosolic nucleic acid sensor that triggers PANoptosis,a form of programmed cell death that integrates pyroptosis,apoptosis,and necroptosis.Although ZBP1 was initially recognized for its role in antiviral defense,recent research has highlighted its importance in the tumor microenvironment(TME),where it is essential for suppressing tumor growth and proliferation.This review explores the multifaceted role of ZBP1 in various cancer types,emphasizing its ability to detect Z-nucleic acids and double-stranded RNAs,leading to the initiation of PANoptosis through receptorinteracting protein homotypic interaction motif(RHIM)-dependent interactions.However,the antitumor potential of ZBP1 involves adenosine deaminase RNA specific 1(ADAR1),particularly its ADAR1-P150 isoform(150 kDa),which inhibits ZBP1-mediated cell death,thereby promoting tumor progression.This has spurred interest in the development of ADAR1 inhibitors and combination therapies with US Food and Drug Administration(FDA)-approved agents such as interferon-α(IFN-α)to increase ZBP1 activity.Promising studies have demonstrated that ZBP1 regulation can significantly impact tumor suppression,particularly in necrotic tumors,where its expression is correlated with reduced tumor growth.Furthermore,oligomerization of telomeric repeat-containing RNA(TERRA)-bound ZBP1 on the mitochondrial membrane has been linked to mitochondrial antiviral signaling(MAVS)-induced interferon responses,adding another layer to the tumor-suppressive functions of ZBP1.Clinical investigations into nuclear export inhibitors(NEIs)such as KPT-330 and KPT-8602,in combination with IFN therapy,have shown potential in harnessing ZBP1 to induce PANoptosis and suppress tumor growth.Additionally,the small molecule curaxin CBL0137 has been identified as a promising agent for reversing immune checkpoint blockade(ICB)resistance by inducing Z-DNA(Z form DNA)formation and ZBP1-mediated necroptosis in tumor fibroblasts.This review consolidates recent advancements in ZBP1 research,highlighting its therapeutic potential as a target for cancer treatment and its promising role in overcoming resistance to existing therapies.展开更多
Background:Sepsis is often accompanied by lactic acidemia and acute lung injury(ALI).Clinical studies have established that high serum lactate levels are associated with increased mortality rates in septic patients.We...Background:Sepsis is often accompanied by lactic acidemia and acute lung injury(ALI).Clinical studies have established that high serum lactate levels are associated with increased mortality rates in septic patients.We further observed a significant correlation between the levels of cold-inducible RNA-binding protein(CIRP)in plasma and bronchoalveolar lavage fluid(BALF),as well as lactate levels,and the severity of post-sepsis ALI.The underlying mechanism,however,remains elusive.Methods:C57BL/6 wild type(WT),Casp8^(-/-),Ripk3^(-/-),and Zbp1^(-/-)mice were subjected to the cecal ligation and puncture(CLP)sepsis model.In this model,we measured intra-macrophage CIRP lactylation and the subsequent release of CIRP.We also tracked the internalization of extracellular CIRP(eCIRP)in pulmonary vascular endothelial cells(PVECs)and its interaction with Z-DNA binding protein 1(ZBP1).Furthermore,we monitored changes in ZBP1 levels in PVECs and the consequent activation of cell death pathways.Results:In the current study,we demonstrate that lactate,accumulating during sepsis,promotes the lactylation of CIRP in macrophages,leading to the release of CIRP.Once eCIRP is internalized by PVEC through a Toll-like receptor 4(TLR4)-mediated endocytosis pathway,it competitively binds to ZBP1 and effectively blocks the interaction between ZBP1 and tripartite motif containing 32(TRIM32),an E3 ubiquitin ligase targeting ZBP1 for proteasomal degradation.This interference mechanism stabilizes ZBP1,thereby enhancing ZBP1-receptor-interacting protein kinase 3(RIPK3)-dependent PVEC PANoptosis,a form of cell death involving the simultaneous activation of multiple cell death pathways,thereby exacerbating ALI.Conclusions:These findings unveil a novel pathway by which lactic acidemia promotes macrophage-derived eCIRP release,which,in turn,mediates ZBP1-dependent PVEC PANoptosis in sepsis-induced ALI.This finding offers new insights into the molecular mechanisms driving sepsis-related pulmonary complications and provides potential new therapeutic strategies.展开更多
Interferons(IFNs)play an important role in immunomodulatory and antiviral functions.IFN-induced necroptosis has been reported in cells deficient in receptor-interacting protein kinase 1(RIPK1),Fas-associated protein w...Interferons(IFNs)play an important role in immunomodulatory and antiviral functions.IFN-induced necroptosis has been reported in cells deficient in receptor-interacting protein kinase 1(RIPK1),Fas-associated protein with death domain(FADD),or caspase-8,but the mechanism is largely unknown.Here,we report that the DNA-dependent activator of IFN regulatory factors(ZBP1,also known as DAI)is required for both type Ⅰ(β)and type Ⅱ(γ)IFN-induced necroptosis.We show that L929 fibroblast cells became susceptible to IFN-induced necroptosis when RIPK1,FADD,or Caspase-8 was genetically deleted,confirming the antinecroptotic role of these proteins in IFN signaling.We found that the pronecroptotic signal from IFN stimulation depends on new protein synthesis and identified ZBP1,an IFN-stimulated gene(ISG)product,as the de novo synthesized protein that triggers necroptosis in IFN-stimulated cells.The N-terminal domain(ND)of ZBP1 is important for ZBP1–ZBP1 homointeraction,and its RHIM domain in the C-terminal region interacts with RIPK3 to initiate RIPK3-dependent necroptosis.The antinecroptotic function of RIPK1,FADD,and caspase-8 in IFN-treated cells is most likely executed by caspase-8-mediated cleavage of RIPK3,since the inhibitory effect on necroptosis was eliminated when the caspase-8 cleavage site in RIPK3 was mutated.ZBP1-mediated necroptosis in IFN-treated cells is likely physiologically relevant,as ZBP1 KO mice were significantly protected against acute systemic inflammatory response syndrome(SIRS)induced by TNF+IFN-γ.展开更多
PANoptosis has been shown to play important pathophysiological roles,particularly in cancer.This review summarizes the composition and functions of PANoptosis and its associated PANoptosomes,including the ZBP1,RIPK1,A...PANoptosis has been shown to play important pathophysiological roles,particularly in cancer.This review summarizes the composition and functions of PANoptosis and its associated PANoptosomes,including the ZBP1,RIPK1,AIM2,and NLRP12-PANoptosomes.Predictive models based on PANoptosis markers have been developed to guide personalized treatment strategies,highlighting novel therapeutic targets.Research into compounds that modulate PANoptosis pathways is ongoing,with the aim of increasing cancer treatment efficacy and addressing challenges such as drug resistance and immune evasion.This review also summarizes innovative PANoptosis-related prognostic gene signature models and compounds that modulate PANoptosis pathways.展开更多
Background: Stroke causes substantial death and disability worldwide, challenging healthcare systems and impacting patients' lives. Research on stroke biomarkers can aid in the development of targeted therapies, w...Background: Stroke causes substantial death and disability worldwide, challenging healthcare systems and impacting patients' lives. Research on stroke biomarkers can aid in the development of targeted therapies, while Zhenbao Pills (ZBP) from traditional Chinese medicine may enhance recovery from neurological disorders. Further investigations into the mechanisms of ZBP are crucial for better stroke management.Methods: This research accessed databases to pinpoint the core components and identify the targets of ZBP and stroke. "Drug-component-target" networks were established, followed by enrichment analysis of identified targets. We also used Mendelian randomization (MR) to assess causal relationships between feature genes and stroke incidence, for which colocalization was employed for validation. Furthermore, molecular docking and Gene Expression Omnibus (GEO) datasets were used for preliminary confirmation.Results: This study identified 14 core components and 105 stroke-related targets for ZBP. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that these targets are involved mainly in oxidative stress processes, lipid metabolism, and the PI3K-Akt signaling pathway. Correlation with stroke risk was determined through MR analysis, which revealed that the VEGFA and ARG1 genes were negatively correlated with stroke risk and GATM was positively correlated. Additionally, the stable interactions of molecular docking and differential expression of key genes support their potential therapeutic relevance.Conclusion: Stroke may be mitigated through essential constituents of ZBP (e.g., luteolin, quercetin, and isorhamnetin) that target pivotal genes (e.g., VEGFA, ARG1, and GATM), including characteristic genes, and the modulation of oxidative stress and inflammation-related pathways. These discoveries hold important implications for clinical practice and future research endeavors.展开更多
Myocardial ischemia-reperfusion(I/R)injury is the primary factor that counteracts the beneficial effects of reperfusion therapy.Cardiomyocyte death serves as the fundamental pathological hallmark of I/R injury.However...Myocardial ischemia-reperfusion(I/R)injury is the primary factor that counteracts the beneficial effects of reperfusion therapy.Cardiomyocyte death serves as the fundamental pathological hallmark of I/R injury.However,targeting a single type of cell death has been reported to be ineffective at preventing I/R injury.ZBP1 is well established as a nucleic acid sensor that activates inflammatory and various cell death signaling pathways.However,the specific role of ZBP1 in adult cardiomyocytes,particularly in the absence of nucleic acid ligands,remains largely unexplored.In this study,our dynamic transcriptomic analyses at various I/R stages revealed a cluster of genes significantly enriched in cell death-related processes,with ZBP1 showing significant expression changes in both our I/R injury mouse model and public human ischemic cardiomyopathy datasets.Cardiomyocytes are the primary cell type expressing ZBP1 in response to I/R injury.Hypoxia/reoxygenation stress induced the upregulation of multiple cell death markers indicative of PANoptosis in adult cardiomyocytes,which was mitigated by ZBP1 deficiency.Compared with treatment with conventional cell death inhibitors,cardiomyocyte-specific Zbp1 deficiency ameliorated I/R-induced PANoptosis,resulting in a more substantial reduction in myocardial infarct size.Conversely,myocardial Zbp1 overexpression in adult mice directly induced cardiac remodeling and heart failure.Mechanistically,ZBP1 drives cardiomyocyte PANoptosis by promoting the formation of the ZBP1/RIPK3/CAS8/CAS6 PANoptosome complex.Virtual screening and experimental validation revealed a novel small-molecule compound,MSB,which has high binding affinity for ZBP1 and effectively attenuates myocardial I/R injury both in vitro and in vivo.Collectively,these findings highlight the role of ZBP1 as a mediator of cardiomyocyte PANoptosis and suggest that targeting ZBP1 could be a promising strategy for mitigating myocardial I/R injury.展开更多
文摘VP22是一种保守的被膜蛋白,广泛存在于伪狂犬病病毒(PRV)和HSV-1等α-疱疹病毒中。HSV-1的VP22是病毒的重要毒力因子,它通过调节病毒蛋白和宿主蛋白的亚细胞定位,增强病毒的神经毒性;HSV-1 VP22还能够抑制AIM2炎症小体的激活,进而促进病毒的复制。然而,PRV VP22与HSV-1 VP22的同源性仅为26%,其在病毒感染和致病中的作用尚不明确。近期,mBio杂志发表了题为“Suppression of ZBP1-mediated NLRP3 inflammasome by the tegument protein VP22 facilitates pseudorabies virus infection”的研究论文,论文的通讯作者为南京农业大学动物医学院姜平教授和刘星教授,第一作者为博士后马梓承。本研究揭示了ZBP1介导的NLRP3炎症小体在PRV感染中的作用,并发现PRV VP22通过抑制该途径介导的炎症反应,促进病毒的复制和致病性。该研究成果为理解PRV复制和致病机制提供了新的视角。
基金supported by the National Natural Science Foundation of China under Grant 22376100.
文摘Z-DNA binding protein 1(ZBP1)has emerged as a critical player in cancer biology,functioning as a cytosolic nucleic acid sensor that triggers PANoptosis,a form of programmed cell death that integrates pyroptosis,apoptosis,and necroptosis.Although ZBP1 was initially recognized for its role in antiviral defense,recent research has highlighted its importance in the tumor microenvironment(TME),where it is essential for suppressing tumor growth and proliferation.This review explores the multifaceted role of ZBP1 in various cancer types,emphasizing its ability to detect Z-nucleic acids and double-stranded RNAs,leading to the initiation of PANoptosis through receptorinteracting protein homotypic interaction motif(RHIM)-dependent interactions.However,the antitumor potential of ZBP1 involves adenosine deaminase RNA specific 1(ADAR1),particularly its ADAR1-P150 isoform(150 kDa),which inhibits ZBP1-mediated cell death,thereby promoting tumor progression.This has spurred interest in the development of ADAR1 inhibitors and combination therapies with US Food and Drug Administration(FDA)-approved agents such as interferon-α(IFN-α)to increase ZBP1 activity.Promising studies have demonstrated that ZBP1 regulation can significantly impact tumor suppression,particularly in necrotic tumors,where its expression is correlated with reduced tumor growth.Furthermore,oligomerization of telomeric repeat-containing RNA(TERRA)-bound ZBP1 on the mitochondrial membrane has been linked to mitochondrial antiviral signaling(MAVS)-induced interferon responses,adding another layer to the tumor-suppressive functions of ZBP1.Clinical investigations into nuclear export inhibitors(NEIs)such as KPT-330 and KPT-8602,in combination with IFN therapy,have shown potential in harnessing ZBP1 to induce PANoptosis and suppress tumor growth.Additionally,the small molecule curaxin CBL0137 has been identified as a promising agent for reversing immune checkpoint blockade(ICB)resistance by inducing Z-DNA(Z form DNA)formation and ZBP1-mediated necroptosis in tumor fibroblasts.This review consolidates recent advancements in ZBP1 research,highlighting its therapeutic potential as a target for cancer treatment and its promising role in overcoming resistance to existing therapies.
基金supported by grants from the USA VA(1I01BX004838 and IK6BX006297)the Shenzhen Science and Technology Program(JCYJ20230807142311024).
文摘Background:Sepsis is often accompanied by lactic acidemia and acute lung injury(ALI).Clinical studies have established that high serum lactate levels are associated with increased mortality rates in septic patients.We further observed a significant correlation between the levels of cold-inducible RNA-binding protein(CIRP)in plasma and bronchoalveolar lavage fluid(BALF),as well as lactate levels,and the severity of post-sepsis ALI.The underlying mechanism,however,remains elusive.Methods:C57BL/6 wild type(WT),Casp8^(-/-),Ripk3^(-/-),and Zbp1^(-/-)mice were subjected to the cecal ligation and puncture(CLP)sepsis model.In this model,we measured intra-macrophage CIRP lactylation and the subsequent release of CIRP.We also tracked the internalization of extracellular CIRP(eCIRP)in pulmonary vascular endothelial cells(PVECs)and its interaction with Z-DNA binding protein 1(ZBP1).Furthermore,we monitored changes in ZBP1 levels in PVECs and the consequent activation of cell death pathways.Results:In the current study,we demonstrate that lactate,accumulating during sepsis,promotes the lactylation of CIRP in macrophages,leading to the release of CIRP.Once eCIRP is internalized by PVEC through a Toll-like receptor 4(TLR4)-mediated endocytosis pathway,it competitively binds to ZBP1 and effectively blocks the interaction between ZBP1 and tripartite motif containing 32(TRIM32),an E3 ubiquitin ligase targeting ZBP1 for proteasomal degradation.This interference mechanism stabilizes ZBP1,thereby enhancing ZBP1-receptor-interacting protein kinase 3(RIPK3)-dependent PVEC PANoptosis,a form of cell death involving the simultaneous activation of multiple cell death pathways,thereby exacerbating ALI.Conclusions:These findings unveil a novel pathway by which lactic acidemia promotes macrophage-derived eCIRP release,which,in turn,mediates ZBP1-dependent PVEC PANoptosis in sepsis-induced ALI.This finding offers new insights into the molecular mechanisms driving sepsis-related pulmonary complications and provides potential new therapeutic strategies.
基金supported by the National Natural Science Foundation of China(81788101)the National Basic Research Program of China(973 Program 2015CB553800)+3 种基金the National Natural Science Foundation of China(31420103910,81630042,31500737,and 31601122)the China Postdoctoral Science Foundation(2018T110638,2017 M620267,and 2015T80680)the 111 Project(B12001)the National Science Foundation of China for Fostering Talents in Basic Research(J1310027).
文摘Interferons(IFNs)play an important role in immunomodulatory and antiviral functions.IFN-induced necroptosis has been reported in cells deficient in receptor-interacting protein kinase 1(RIPK1),Fas-associated protein with death domain(FADD),or caspase-8,but the mechanism is largely unknown.Here,we report that the DNA-dependent activator of IFN regulatory factors(ZBP1,also known as DAI)is required for both type Ⅰ(β)and type Ⅱ(γ)IFN-induced necroptosis.We show that L929 fibroblast cells became susceptible to IFN-induced necroptosis when RIPK1,FADD,or Caspase-8 was genetically deleted,confirming the antinecroptotic role of these proteins in IFN signaling.We found that the pronecroptotic signal from IFN stimulation depends on new protein synthesis and identified ZBP1,an IFN-stimulated gene(ISG)product,as the de novo synthesized protein that triggers necroptosis in IFN-stimulated cells.The N-terminal domain(ND)of ZBP1 is important for ZBP1–ZBP1 homointeraction,and its RHIM domain in the C-terminal region interacts with RIPK3 to initiate RIPK3-dependent necroptosis.The antinecroptotic function of RIPK1,FADD,and caspase-8 in IFN-treated cells is most likely executed by caspase-8-mediated cleavage of RIPK3,since the inhibitory effect on necroptosis was eliminated when the caspase-8 cleavage site in RIPK3 was mutated.ZBP1-mediated necroptosis in IFN-treated cells is likely physiologically relevant,as ZBP1 KO mice were significantly protected against acute systemic inflammatory response syndrome(SIRS)induced by TNF+IFN-γ.
基金This study was supported by the National Natural Science Foundation of China(82273963)the 2023 Annual Graduate Students Innovation Fund from Tianjin University of Traditional Chinese Medicine(YJSKC-20231015)the 2022 Annual Graduate Students Innovation Fund from the School of Integrative Medicine,Tianjin University of Traditional Chinese Medicine(ZXYCXLX202211).
文摘PANoptosis has been shown to play important pathophysiological roles,particularly in cancer.This review summarizes the composition and functions of PANoptosis and its associated PANoptosomes,including the ZBP1,RIPK1,AIM2,and NLRP12-PANoptosomes.Predictive models based on PANoptosis markers have been developed to guide personalized treatment strategies,highlighting novel therapeutic targets.Research into compounds that modulate PANoptosis pathways is ongoing,with the aim of increasing cancer treatment efficacy and addressing challenges such as drug resistance and immune evasion.This review also summarizes innovative PANoptosis-related prognostic gene signature models and compounds that modulate PANoptosis pathways.
基金funded by the 2021 Inner Mongolia Higher Education Scientific Research Project(NJZY21063)the 2023 Project of the Natural Science Foundation of the Inner Mongolia Autonomous Region(2023LHMS08081).
文摘Background: Stroke causes substantial death and disability worldwide, challenging healthcare systems and impacting patients' lives. Research on stroke biomarkers can aid in the development of targeted therapies, while Zhenbao Pills (ZBP) from traditional Chinese medicine may enhance recovery from neurological disorders. Further investigations into the mechanisms of ZBP are crucial for better stroke management.Methods: This research accessed databases to pinpoint the core components and identify the targets of ZBP and stroke. "Drug-component-target" networks were established, followed by enrichment analysis of identified targets. We also used Mendelian randomization (MR) to assess causal relationships between feature genes and stroke incidence, for which colocalization was employed for validation. Furthermore, molecular docking and Gene Expression Omnibus (GEO) datasets were used for preliminary confirmation.Results: This study identified 14 core components and 105 stroke-related targets for ZBP. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that these targets are involved mainly in oxidative stress processes, lipid metabolism, and the PI3K-Akt signaling pathway. Correlation with stroke risk was determined through MR analysis, which revealed that the VEGFA and ARG1 genes were negatively correlated with stroke risk and GATM was positively correlated. Additionally, the stable interactions of molecular docking and differential expression of key genes support their potential therapeutic relevance.Conclusion: Stroke may be mitigated through essential constituents of ZBP (e.g., luteolin, quercetin, and isorhamnetin) that target pivotal genes (e.g., VEGFA, ARG1, and GATM), including characteristic genes, and the modulation of oxidative stress and inflammation-related pathways. These discoveries hold important implications for clinical practice and future research endeavors.
基金supported by the National Natural Science Foundation(grant number 82130010 to Aijun Sun)the Innovation Program of the Shanghai Municipal Education Commission(to Aijun Sun)and the Basic Science Center Project(grant number T2288101 to Junbo Ge)supported by the Medical Science Data Center of Fudan University.
文摘Myocardial ischemia-reperfusion(I/R)injury is the primary factor that counteracts the beneficial effects of reperfusion therapy.Cardiomyocyte death serves as the fundamental pathological hallmark of I/R injury.However,targeting a single type of cell death has been reported to be ineffective at preventing I/R injury.ZBP1 is well established as a nucleic acid sensor that activates inflammatory and various cell death signaling pathways.However,the specific role of ZBP1 in adult cardiomyocytes,particularly in the absence of nucleic acid ligands,remains largely unexplored.In this study,our dynamic transcriptomic analyses at various I/R stages revealed a cluster of genes significantly enriched in cell death-related processes,with ZBP1 showing significant expression changes in both our I/R injury mouse model and public human ischemic cardiomyopathy datasets.Cardiomyocytes are the primary cell type expressing ZBP1 in response to I/R injury.Hypoxia/reoxygenation stress induced the upregulation of multiple cell death markers indicative of PANoptosis in adult cardiomyocytes,which was mitigated by ZBP1 deficiency.Compared with treatment with conventional cell death inhibitors,cardiomyocyte-specific Zbp1 deficiency ameliorated I/R-induced PANoptosis,resulting in a more substantial reduction in myocardial infarct size.Conversely,myocardial Zbp1 overexpression in adult mice directly induced cardiac remodeling and heart failure.Mechanistically,ZBP1 drives cardiomyocyte PANoptosis by promoting the formation of the ZBP1/RIPK3/CAS8/CAS6 PANoptosome complex.Virtual screening and experimental validation revealed a novel small-molecule compound,MSB,which has high binding affinity for ZBP1 and effectively attenuates myocardial I/R injury both in vitro and in vivo.Collectively,these findings highlight the role of ZBP1 as a mediator of cardiomyocyte PANoptosis and suggest that targeting ZBP1 could be a promising strategy for mitigating myocardial I/R injury.
