The N-end rule pathway is a unique branch of the ubiquitin-proteasome system in which the determination of a protein＇s half-life is dependent on its N-terminal residue. The N-terminal residue serves as the degradatio...The N-end rule pathway is a unique branch of the ubiquitin-proteasome system in which the determination of a protein＇s half-life is dependent on its N-terminal residue. The N-terminal residue serves as the degradation signal of a protein and thus called N-degron. N-degron can be recognized and modifed by several steps of post-translational modifications, such as oxidation, deamination, arginylation or acetylation, it then polyubiquitinated by the N-recognin for degradation. The molecular basis of the N-end rule pathway has been elucidated and its physiological functions have been revealed in the past 30 years. This pathway is involved in several biological aspects, including transcription, differentiation, chromosomal segregation, genome stability, apoptosis, mitochondrial quality control, cardiovascular development, neurogenesis, carcinogenesis, and spermatogenesis. Disturbance of this pathway often causes the failure of these processes, resulting in some human diseases. This review summarized the physiological functions of the N-end rule pathway, introduced the related biological processes and diseases, with an emphasis on the inner link between this pathway and certain symptoms.展开更多
The N-end rule pathway regulates protein degradation, which depends on exposed N-terminal sequences in prokaryotes and eukaryotes. In plants, conserved and specific enzymes stimulate selective proteolysis. Although a ...The N-end rule pathway regulates protein degradation, which depends on exposed N-terminal sequences in prokaryotes and eukaryotes. In plants, conserved and specific enzymes stimulate selective proteolysis. Although a number of developmental and growth phenotypes have been reported for mutants in the N-end rule, its function has remained unrelated to specific physiological pathways. The first report of the direct involvement of the N-end rule in stress responses focused on hypoxic signaling and how the oxygen-dependent oxidation of cystein promotes the N-end rule-mediated degradation of ethylene responsive factor （ERF）-VII proteins, the master regulators of anaerobic responses. It has been suggested that plants have evolved specific mechanisms to tune ERF-VII availability in the nucleus. In this review, we speculate that ERF-VII proteins are reversibly protected from degradation via membrane sequestration. The oxidative response in plants subjected to anoxic conditions suggests that reactive oxygen and nitrogen species （reactive oxygen species and reactive nitrogen species） may interact or interfere with the N-end rule pathway-mediated response to hypoxia.展开更多
目的:探讨血清高敏C反应蛋白(hsCRP)水平与致心律失常性心肌病(ACM)患者临床特征及预后的关系,评估其对终末期心力衰竭事件(ESHF)风险的预测价值。方法:回顾性纳入临界诊断及确诊ACM的患者328例,根据基线hsCRP实验室标准分为低水平组(≤...目的:探讨血清高敏C反应蛋白(hsCRP)水平与致心律失常性心肌病(ACM)患者临床特征及预后的关系,评估其对终末期心力衰竭事件(ESHF)风险的预测价值。方法:回顾性纳入临界诊断及确诊ACM的患者328例,根据基线hsCRP实验室标准分为低水平组(≤3 mg/L,251例)和高水平组(>3 mg/L,77例)。收集病史、检查及检验资料,并比较2组间差异。采用Spearman相关分析、受试者工作特征(ROC)曲线分析、Kaplan-Meier生存分析及Cox比例风险模型评估hsCRP与心功能关联及对ESHF的预测价值。结果:研究人群中,男性占68.9%,致病/可能致病基因突变检出率为44.8%。hsCRP高水平组患者心功能及左室射血分数(LVEF)较差,右心室扩张与氨基末端B型利钠肽前体(NT-proBNP)水平显著升高(P均<0.05),但既往恶性室性心律失常发生率比较,差异无统计学意义(P>0.05)。Spearman相关性分析显示,hsCRP与LVEF呈负相关(r=-0.257,P<0.001),与NT-proBNP(r=0.307,P<0.001)及右心室内径(r=0.115,P=0.039)呈正相关。基因阳性及阴性患者hsCRP水平相近,但在不同心室受累患者中分布不同,在双心室受累患者中水平更高(趋势P=0.005)。ROC曲线分析示,hsCRP预测1、3及5年ESHF事件的曲线下面积(AUC)分别为0.640、0.662、0.654。Kaplan-Meier分析示,hsCRP高水平组随访期间无ESHF生存率显著降低(平均生存97.2 vs 150.5个月,P<0.001)。多因素Cox回归示,hsCRP分别独立于传统心室结构及心力衰竭指标(LVEF、右心室扩张及NT-proBNP)与ESHF风险显著相关(hsCRP作连续及分类变量,P均<0.05)。矫正年龄、性别、NT-proBNP及右心室扩张后,hsCRP水平仍与ESHF风险独立相关(连续变量HR:1.071,95%CI:1.011~1.135,P=0.020;分类变量HR:1.833,95%CI:1.115~3.014,P=0.017)。结论:血清hsCRP升高与ACM患者的心力衰竭和不良结局密切相关,可作为潜在生物标志物用于辅助ACM患者未来ESHF事件的预测。展开更多
基金This work was supported by the National Natural Science Foundation of China （Nos. 31471277 and 91519317）.
文摘The N-end rule pathway is a unique branch of the ubiquitin-proteasome system in which the determination of a protein＇s half-life is dependent on its N-terminal residue. The N-terminal residue serves as the degradation signal of a protein and thus called N-degron. N-degron can be recognized and modifed by several steps of post-translational modifications, such as oxidation, deamination, arginylation or acetylation, it then polyubiquitinated by the N-recognin for degradation. The molecular basis of the N-end rule pathway has been elucidated and its physiological functions have been revealed in the past 30 years. This pathway is involved in several biological aspects, including transcription, differentiation, chromosomal segregation, genome stability, apoptosis, mitochondrial quality control, cardiovascular development, neurogenesis, carcinogenesis, and spermatogenesis. Disturbance of this pathway often causes the failure of these processes, resulting in some human diseases. This review summarized the physiological functions of the N-end rule pathway, introduced the related biological processes and diseases, with an emphasis on the inner link between this pathway and certain symptoms.
文摘The N-end rule pathway regulates protein degradation, which depends on exposed N-terminal sequences in prokaryotes and eukaryotes. In plants, conserved and specific enzymes stimulate selective proteolysis. Although a number of developmental and growth phenotypes have been reported for mutants in the N-end rule, its function has remained unrelated to specific physiological pathways. The first report of the direct involvement of the N-end rule in stress responses focused on hypoxic signaling and how the oxygen-dependent oxidation of cystein promotes the N-end rule-mediated degradation of ethylene responsive factor （ERF）-VII proteins, the master regulators of anaerobic responses. It has been suggested that plants have evolved specific mechanisms to tune ERF-VII availability in the nucleus. In this review, we speculate that ERF-VII proteins are reversibly protected from degradation via membrane sequestration. The oxidative response in plants subjected to anoxic conditions suggests that reactive oxygen and nitrogen species （reactive oxygen species and reactive nitrogen species） may interact or interfere with the N-end rule pathway-mediated response to hypoxia.
文摘目的:探讨血清高敏C反应蛋白(hsCRP)水平与致心律失常性心肌病(ACM)患者临床特征及预后的关系,评估其对终末期心力衰竭事件(ESHF)风险的预测价值。方法:回顾性纳入临界诊断及确诊ACM的患者328例,根据基线hsCRP实验室标准分为低水平组(≤3 mg/L,251例)和高水平组(>3 mg/L,77例)。收集病史、检查及检验资料,并比较2组间差异。采用Spearman相关分析、受试者工作特征(ROC)曲线分析、Kaplan-Meier生存分析及Cox比例风险模型评估hsCRP与心功能关联及对ESHF的预测价值。结果:研究人群中,男性占68.9%,致病/可能致病基因突变检出率为44.8%。hsCRP高水平组患者心功能及左室射血分数(LVEF)较差,右心室扩张与氨基末端B型利钠肽前体(NT-proBNP)水平显著升高(P均<0.05),但既往恶性室性心律失常发生率比较,差异无统计学意义(P>0.05)。Spearman相关性分析显示,hsCRP与LVEF呈负相关(r=-0.257,P<0.001),与NT-proBNP(r=0.307,P<0.001)及右心室内径(r=0.115,P=0.039)呈正相关。基因阳性及阴性患者hsCRP水平相近,但在不同心室受累患者中分布不同,在双心室受累患者中水平更高(趋势P=0.005)。ROC曲线分析示,hsCRP预测1、3及5年ESHF事件的曲线下面积(AUC)分别为0.640、0.662、0.654。Kaplan-Meier分析示,hsCRP高水平组随访期间无ESHF生存率显著降低(平均生存97.2 vs 150.5个月,P<0.001)。多因素Cox回归示,hsCRP分别独立于传统心室结构及心力衰竭指标(LVEF、右心室扩张及NT-proBNP)与ESHF风险显著相关(hsCRP作连续及分类变量,P均<0.05)。矫正年龄、性别、NT-proBNP及右心室扩张后,hsCRP水平仍与ESHF风险独立相关(连续变量HR:1.071,95%CI:1.011~1.135,P=0.020;分类变量HR:1.833,95%CI:1.115~3.014,P=0.017)。结论:血清hsCRP升高与ACM患者的心力衰竭和不良结局密切相关,可作为潜在生物标志物用于辅助ACM患者未来ESHF事件的预测。
