非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)逐渐成为发病率最高的慢性肝病类型。NASH发病常常伴随全身代谢综合征,疾病进展具有发生肝硬化甚至肝癌的高风险。然而,目前临床上尚无一种获批的针对NASH的有效治疗药物。我们...非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)逐渐成为发病率最高的慢性肝病类型。NASH发病常常伴随全身代谢综合征,疾病进展具有发生肝硬化甚至肝癌的高风险。然而,目前临床上尚无一种获批的针对NASH的有效治疗药物。我们的最新研究结果发现,天然免疫重要分子CFLAR[CASP8 and FADD(Fas-associating protein with death domain)-like apoptosis regulator]直在NASH疾病进程中的关键负调控作用。深入的分子机制探索证实,CFLAR接靶向激酶MAP3K5[mitogen-activated protein kinase kinase kinase 5,也称为ASK1(apoptosis signal-regulating kinase 1)]并阻断其N-端二聚化,从而抑制ASK1和激酶MAPK8[mitogen-activated protein kinase 8,也称为JNK1(c-Jun N-terminal kinase 1)]的信号通路。此外,我们鉴定出源于CFLAR的一个小肽片段(S1)可以有效发挥CFLAR对ASK1的抑制作用。应用CFLAR(S1)治疗可有效改善并逆转小鼠和猴子中的NASH及并发的代谢综合征。综上所述,我们发现,CFLAR是控制NASH疾病进展的关键抑制子。CFLAR(S1)特异性抑制ASK 1激活的作用机制,为开发或筛选NASH的靶向治疗药物提供了可行的新方案。展开更多
Jasmonates are a new class of plant hormones that play important roles in plant development and plant defense. The COI1 gene was previously shown to be required for jasmonate- regulated plant fertility and defense. We...Jasmonates are a new class of plant hormones that play important roles in plant development and plant defense. The COI1 gene was previously shown to be required for jasmonate- regulated plant fertility and defense. We demonstrated for the first time that COI1 interacts with the Arabidopsis SKP1-LIKE1 (ASK1) to form a complex that is required for jasmonate action in planta. Functional analysis by antisense strategy showed that ASK1 is involved in male fertility.展开更多
Stress-induced retrograde signal transmission from the plastids to the nucleus has long puzzled plant biologists.To address this,we performed a suppressor screen of the ceh1 mutant,which contains elevated 2-C-methyl-d...Stress-induced retrograde signal transmission from the plastids to the nucleus has long puzzled plant biologists.To address this,we performed a suppressor screen of the ceh1 mutant,which contains elevated 2-C-methyl-d-erythritol-2,4-cyclopyrophosphate(MEcPP)levels,and identified the gain-of-function mutant impα-9,which shows reversed dwarfism and suppressed expression of stress-response genes in the ceh1 background despite heightened MEcPP.Subsequent genetic and biochemical analyses established that the accumulation of MEcPP initiates an upsurge in Arabidopsis SKP1-like 1(ASK1)abundance,a pivotal component in the proteasome degradation pathway.This increase in ASK1 prompts the degradation of IMPα-9.Moreover,we uncovered a protein-protein interaction between IMPα-9 and TPR2,a transcriptional co-suppressor and found that a reduction in IMPα-9 levels coincides with a decrease in TPR2 abundance.Significantly,the interaction between IMPα-9 and TPR2 was disrupted in impα-9 mutants,highlighting the critical role of a single amino acid alteration in maintaining their association.Disruption of their interaction results in the reversal of MEcPP-associated phenotypes.Chromatin immunoprecipitation coupled with sequencing analyses revealed that TPR2 binds globally to stress-response genes and suggested that IMPα-9 associates with the chromatin.They function together to suppress the expression of stress-response genes under normal conditions,but this suppression is alleviated in response to stress through the degradation of the suppressing machinery.The biological relevance of our discoveries was validated under high light stress,marked by MEcPP accumulation,elevated ASK1 levels,IMPα-9 degredation,reduced TPR2 abundance,and subsequent activation of a network of stress-response genes.In summary,our study collectively unveils fresh insights into plant adaptive mechanisms,highlighting intricate interactions among retrograde signaling,the proteasome,and nuclear transport machinery.展开更多
Background: Hepatic ischemia-reperfusion injury (HIRI) stands as an unavoidable complication arising from liver surgery, profoundly intertwined with its prognosis. The role of lysine methyltransferase SET domain bifur...Background: Hepatic ischemia-reperfusion injury (HIRI) stands as an unavoidable complication arising from liver surgery, profoundly intertwined with its prognosis. The role of lysine methyltransferase SET domain bifurcated 1 (SETDB1) in HIRI remains elusive, despite its confirmation as a potential therapeutic target for diverse diseases. Here, we investigated the mechanism by which SETDB1 regulated HIRI. Methods: RNA sequencing data were used to identify the expression and potential targets of SETDB1 through bioinformatics analysis. To elucidate the impact of SETDB1 on HIRI, both an in vivo model of HIRI in mice and an in vitro model of hepatocyte hypoxia/reoxygenation were established. Biochemical and histological analyses were used to investigate the influence of SETDB1 on liver damage mediated by HIRI. Chromatin immunoprecipitation and coimmunoprecipitation were implemented to explore the in-depth mechanism of SETDB1 regulating HIRI. Results: We confirmed that hepatocellular SETDB1 was up-regulated during HIRI and had a close correlation with HIRI-related inflammation and apoptosis. Moreover, inhibition of SETDB1 could mitigate HIRI-induced liver damage, inflammation, and apoptosis. Through our comprehensive mechanistic investigation, we revealed that SETDB1 interacts with apoptosis-signal-regulating kinase 1 (ASK1) and facilitates the methylation of its lysine residues. Inhibition of SETDB1 resulted in reduced phosphorylation of ASK1, leading to a marked suppression of downstream c-Jun N-terminal kinase (JNK)/p38 signaling pathway activation. The therapeutic effect on inflammation and apoptosis achieved through SETDB1 inhibition was nullified by the restoration of JNK/p38 signaling activation through ASK1 overexpression. Conclusions: The findings from our study indicate that SETDB1 mediates lysine methylation of ASK1 and modulates the activation of the ASK1–JNK/p38 pathway, thus involved in HIRI-induced inflammation and apoptosis. These results suggest that SETDB1 holds promise as a potential therapeutic ta展开更多
H-Ras is well known as one of the essential components of Ras/Raf/MEK/ERK cascade, which is a critical prosurvival signaling mechanism in most eukaryotic cells. Ras targets Raf/MEK/ERK cascade by integrating and trans...H-Ras is well known as one of the essential components of Ras/Raf/MEK/ERK cascade, which is a critical prosurvival signaling mechanism in most eukaryotic cells. Ras targets Raf/MEK/ERK cascade by integrating and transmitting extracellular signals from growth factor receptors to Raf, leading to the propagation of signals to modulate a serious of cellular survival events. Apoptosis signal-regulating kinasel (ASK1) serves as a general mediator of cell death because it is responsive to a variety of death signals. In this study, we found that H-Ras interacted with ASK1 to cause the inhibition of both ASK1 activity and ASK1-induced apoptosis in vivo, which was reversed only partially by addition of RafS621A, an antagonist of Raf, whereas MEK inhibitor, PD98059, and PI3K inhibitor, LY294002, did not disturb the inhibitory effect of H-Ras on ASK-1-induced apoptosis. Furthermore, by means of immunoprecipitate and kinase assays, we demonstrated that the interaction between H-Ras and ASK1 as well as the inhibition of ASK1 activity were dependent on the binding activity of H-Ras. These results suggest that a novel mechanism may be involved in H-Rasmediated cell survival in addition to the well established MEK/ERK and PI3K/Akt kinase-dependent enhancement of cell survival.展开更多
文摘非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)逐渐成为发病率最高的慢性肝病类型。NASH发病常常伴随全身代谢综合征,疾病进展具有发生肝硬化甚至肝癌的高风险。然而,目前临床上尚无一种获批的针对NASH的有效治疗药物。我们的最新研究结果发现,天然免疫重要分子CFLAR[CASP8 and FADD(Fas-associating protein with death domain)-like apoptosis regulator]直在NASH疾病进程中的关键负调控作用。深入的分子机制探索证实,CFLAR接靶向激酶MAP3K5[mitogen-activated protein kinase kinase kinase 5,也称为ASK1(apoptosis signal-regulating kinase 1)]并阻断其N-端二聚化,从而抑制ASK1和激酶MAPK8[mitogen-activated protein kinase 8,也称为JNK1(c-Jun N-terminal kinase 1)]的信号通路。此外,我们鉴定出源于CFLAR的一个小肽片段(S1)可以有效发挥CFLAR对ASK1的抑制作用。应用CFLAR(S1)治疗可有效改善并逆转小鼠和猴子中的NASH及并发的代谢综合征。综上所述,我们发现,CFLAR是控制NASH疾病进展的关键抑制子。CFLAR(S1)特异性抑制ASK 1激活的作用机制,为开发或筛选NASH的靶向治疗药物提供了可行的新方案。
基金This work was in part supported by the Foundation of Visiting Scientist of the Key Laboratory of University, Foundation of the Union Research Center of Hunan Life Sciences Hunan Natural Science Foundation
文摘Jasmonates are a new class of plant hormones that play important roles in plant development and plant defense. The COI1 gene was previously shown to be required for jasmonate- regulated plant fertility and defense. We demonstrated for the first time that COI1 interacts with the Arabidopsis SKP1-LIKE1 (ASK1) to form a complex that is required for jasmonate action in planta. Functional analysis by antisense strategy showed that ASK1 is involved in male fertility.
基金supported by National Institutes of Health National Institutes of Health(NIH)R01GM107311-8National Science Foundation National Science Foundation(NSF)2104365 grantsby Dr.John W.Leibacher and Mrs.Kathy Cookson endowed chair funds to K.D.
文摘Stress-induced retrograde signal transmission from the plastids to the nucleus has long puzzled plant biologists.To address this,we performed a suppressor screen of the ceh1 mutant,which contains elevated 2-C-methyl-d-erythritol-2,4-cyclopyrophosphate(MEcPP)levels,and identified the gain-of-function mutant impα-9,which shows reversed dwarfism and suppressed expression of stress-response genes in the ceh1 background despite heightened MEcPP.Subsequent genetic and biochemical analyses established that the accumulation of MEcPP initiates an upsurge in Arabidopsis SKP1-like 1(ASK1)abundance,a pivotal component in the proteasome degradation pathway.This increase in ASK1 prompts the degradation of IMPα-9.Moreover,we uncovered a protein-protein interaction between IMPα-9 and TPR2,a transcriptional co-suppressor and found that a reduction in IMPα-9 levels coincides with a decrease in TPR2 abundance.Significantly,the interaction between IMPα-9 and TPR2 was disrupted in impα-9 mutants,highlighting the critical role of a single amino acid alteration in maintaining their association.Disruption of their interaction results in the reversal of MEcPP-associated phenotypes.Chromatin immunoprecipitation coupled with sequencing analyses revealed that TPR2 binds globally to stress-response genes and suggested that IMPα-9 associates with the chromatin.They function together to suppress the expression of stress-response genes under normal conditions,but this suppression is alleviated in response to stress through the degradation of the suppressing machinery.The biological relevance of our discoveries was validated under high light stress,marked by MEcPP accumulation,elevated ASK1 levels,IMPα-9 degredation,reduced TPR2 abundance,and subsequent activation of a network of stress-response genes.In summary,our study collectively unveils fresh insights into plant adaptive mechanisms,highlighting intricate interactions among retrograde signaling,the proteasome,and nuclear transport machinery.
基金Financial support for this study was provided by the National Natural Science Foundation of China(grant nos.81870067 and 82170664).
文摘Background: Hepatic ischemia-reperfusion injury (HIRI) stands as an unavoidable complication arising from liver surgery, profoundly intertwined with its prognosis. The role of lysine methyltransferase SET domain bifurcated 1 (SETDB1) in HIRI remains elusive, despite its confirmation as a potential therapeutic target for diverse diseases. Here, we investigated the mechanism by which SETDB1 regulated HIRI. Methods: RNA sequencing data were used to identify the expression and potential targets of SETDB1 through bioinformatics analysis. To elucidate the impact of SETDB1 on HIRI, both an in vivo model of HIRI in mice and an in vitro model of hepatocyte hypoxia/reoxygenation were established. Biochemical and histological analyses were used to investigate the influence of SETDB1 on liver damage mediated by HIRI. Chromatin immunoprecipitation and coimmunoprecipitation were implemented to explore the in-depth mechanism of SETDB1 regulating HIRI. Results: We confirmed that hepatocellular SETDB1 was up-regulated during HIRI and had a close correlation with HIRI-related inflammation and apoptosis. Moreover, inhibition of SETDB1 could mitigate HIRI-induced liver damage, inflammation, and apoptosis. Through our comprehensive mechanistic investigation, we revealed that SETDB1 interacts with apoptosis-signal-regulating kinase 1 (ASK1) and facilitates the methylation of its lysine residues. Inhibition of SETDB1 resulted in reduced phosphorylation of ASK1, leading to a marked suppression of downstream c-Jun N-terminal kinase (JNK)/p38 signaling pathway activation. The therapeutic effect on inflammation and apoptosis achieved through SETDB1 inhibition was nullified by the restoration of JNK/p38 signaling activation through ASK1 overexpression. Conclusions: The findings from our study indicate that SETDB1 mediates lysine methylation of ASK1 and modulates the activation of the ASK1–JNK/p38 pathway, thus involved in HIRI-induced inflammation and apoptosis. These results suggest that SETDB1 holds promise as a potential therapeutic ta
文摘H-Ras is well known as one of the essential components of Ras/Raf/MEK/ERK cascade, which is a critical prosurvival signaling mechanism in most eukaryotic cells. Ras targets Raf/MEK/ERK cascade by integrating and transmitting extracellular signals from growth factor receptors to Raf, leading to the propagation of signals to modulate a serious of cellular survival events. Apoptosis signal-regulating kinasel (ASK1) serves as a general mediator of cell death because it is responsive to a variety of death signals. In this study, we found that H-Ras interacted with ASK1 to cause the inhibition of both ASK1 activity and ASK1-induced apoptosis in vivo, which was reversed only partially by addition of RafS621A, an antagonist of Raf, whereas MEK inhibitor, PD98059, and PI3K inhibitor, LY294002, did not disturb the inhibitory effect of H-Ras on ASK-1-induced apoptosis. Furthermore, by means of immunoprecipitate and kinase assays, we demonstrated that the interaction between H-Ras and ASK1 as well as the inhibition of ASK1 activity were dependent on the binding activity of H-Ras. These results suggest that a novel mechanism may be involved in H-Rasmediated cell survival in addition to the well established MEK/ERK and PI3K/Akt kinase-dependent enhancement of cell survival.
