细胞自噬参考.ppt.ppt

系统生物学细胞生物学分子生物学系统生物学细胞生物学分子生物学细胞生物学细胞增殖细胞分化细胞死亡：形式有几种？细胞死亡的分类 非程序性细胞死亡：Necrosis 程序性细胞死亡基于机制的分类：Apoptosis（已学）自噬性程序性细胞死亡（这次课的重点细胞自嗜）Paraptosis：形态学特征细胞浆空泡化，线粒体和内质网肿胀，但没有核固缩现象。现在Paraptosis的文献报道比较少，其机制有待于进一步深入研究。细胞有丝分裂灾难：DNA发生损害时，细胞无法进行完全的分裂从而导致四倍体或多倍体的现象。胀亡(Oncosis)：特征细胞肿胀，体积增大，胞浆空泡化，肿胀波及细胞核、内质网、线粒体等胞内结构，胞膜起泡，细胞膜完整性破坏，周围有明显炎症反应。发生的机制研究尚少，有研究者认为胀亡只是坏死前的一个被动性死亡阶段，但是近年来的研究更倾向于胀亡是一个程序性的死亡方式细胞自嗜（autophagy is a process by which cells undergo partial autodigestion that prolongs survival for a short time under starvation conditions.It provides nutrients that are necessary to maintain cell viability.autophagy is also involved in the killing of bacteria that are ingested by cells.细胞生存的一种机制,在很多生理过程如清除损伤、衰老细胞器以及冗余蛋白上发挥着重要作用Autophagy细胞正常生理活动中，自噬维持在一个非常低的水平保持细胞稳态细胞处于饥饿和营养因子缺乏环境、进行结构调整、降解胞内代谢产物及损伤细胞器时，细胞内的自噬水平迅速上调（诱导因素：营养和能量缺乏、氧化应激、感染、蛋白质大量聚集）Autophagythe proteasome breaks down ubiquitinated proteins,but it may not recognize misfolded proteins and protein aggregates细胞自噬过程细胞自噬过程细胞自噬的分子机制1.1.参与自噬体形成的两个泛素样蛋白系统：参与自噬体形成的两个泛素样蛋白系统：分别由分别由Atg3、Atg5、Atg7、Atg10、Atg12和和LC3参与组成参与组成Atg12 首先由首先由E1 酶酶 Atg7 活化，之后转运至活化，之后转运至 E2 酶酶 Atg10，最后与，最后与Atg5 结合结合,形成自噬体前体形成自噬体前体(autophagosomal precursor)；LC3-也被也被 Atg7 活化，转运至第二种活化，转运至第二种 E2 酶酶 Atg3，并被修，并被修饰成膜结合形式饰成膜结合形式 LC3-。LC3-定位于前自噬定位于前自噬体和自噬体体和自噬体自噬体的标志分子（自噬体的标志分子（LC3 是酵是酵母细胞自噬相关基因母细胞自噬相关基因 Atg8 的类似物的类似物）细胞自噬的分子机制2.型磷脂酰肌醇三磷酸激酶（ClassPI3K）PI3 kinase type III,which includes Atg6 in its complex,promotes the nucleation of autophagic vesicles.Physiological Functions of AutophagyAutophagy Defends against Metabolic StressAutophagy Works as a Cellular HousekeeperAutophagy May Be a Guardian of the GenomeAutophagy in Life and Death Decisions of the Cell1.Autophagy Defends against Metabolic StressAutophagy is activated as an adaptive catabolic process in response to different forms of metabolic stress:nutrient deprivationgrowth factor depletionhypoxia2.Autophagy Works as a Cellular HousekeeperHousekeeping functions performed by autophagy includes:the elimination of defective proteins and organelles the prevention of abnormal protein aggregate accumulation the removal of intracellular pathogensCritical for autophagy-mediated protection against aging,cancer,neurodegenerative diseases,and infection3.Autophagy May Be a Guardian of the GenomeAutophagy-defective cells:genomic instability.Related to:failure to control the damage of checkpoint or repair proteins,deregulated turnover of centrosomes,insuficient energy for proper DNA replication and repairexcessive generation of reactive oxygen species due to ineficient removal of damaged mitochondriaThe precise mechanisms are unclear4.Autophagy in Life and Death Decisions of the CellAutophagy can independently inluence life and death decisions of the cell(by being cytoprotective or selfdestructive),it is also intricately linked to apoptotic death pathwaysFactors that may control the cellular“decision”between the autophagy and apoptosis include:potentially variable thresholds for each processmolecular links that coordinately regulate apoptosis and autophagymutual inhibition or activation of each pathway by the otherAutophagy in DiseaseAutophagy and Neurodegenerative DiseasesAutophagy and Liver DiseaseAutophagy and Muscle DiseaseAutophagy and Cardiac DiseaseAutophagy and CancerAutophagy and AgingAutophagy in Infection,Immunity,and Inlammatory Diseases1.Autophagy and Neurodegenerative DiseasesAutophagy functions as a quality-control system that targets oligomeric(低聚物,低聚体)proteinsSubstrates need to be unfolded to pass through the narrow pore of the proteasomal barrel,oligomeric and aggregated proteins are poor substrates for proteasomal degradation and better targets for autophagic degradationAutophagy activation reduces the formation of protein aggregates and the neurotoxicity of aggregate-prone proteins2.Autophagy and Liver DiseaseProtein quality-control function may be important in the pathogenesis of the most common genetic cause of human liver diseaseA broader question of biomedical relevance is whether the protein quality-control function of autophagy plays a more general role in protecting the liver against alcohol and other hepatotoxic agents3.Autophagy and Muscle Disease Pathogenesis of myodegenerative diseases involve:the failure of autophagosomes to fuse with lysosomesthe aggregation of misfolded proteins that exceed the autophagic clearance capacity of the myocyte4.Autophagy and Cardiac DiseaseAutophagy may constitute an important physiological or pathophysiological response to cardiac stresses ischemia or pressure overloadcoronary artery diseasehypertensionaortic valvular diseasecongestive heart failureCardiomyocyte(similar to the neuron)is a postmitotic cell in which basal autophagy may be important in protein and organelle quality control5.Autophagy and CancerAutophagy is a tumor suppressor pathwaystrong correlation between：molecules that are involved in autophagy induction and tumor suppression molecules that are involved in autophagy inhibition and oncogenesi