autophagy and immunity jianzhong chen institute of immunology zhejiang university school of medicine...
TRANSCRIPT
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Autophagy and Immunity
Jianzhong Chen
Institute of ImmunologyZhejiang University School of Medicine
Nov 1, 2013
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Phagy = eating/lysosomal degradation
Autophagy = self-eating
Mechanism of breakdown of cytoplasm within
the lysosome
Autophagy: a basic cellular process in
eukaryotes
细胞在外界环境因素的影响下,对其内部受损的细胞器、错误折叠的蛋白质及侵入其内的病原体进行降解的过程。
Autophagy
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发现
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发现 比利时科学家 Christian de Duve 在上世纪 5
0 年代通过电镜观察到自噬体结构,并且在 1963 年溶酶体国际会议上首先提出了“自噬”这种说法。因此 Christian de Duve 被公认为自噬研究的鼻祖。 Christian de Duve 也因发现溶酶体,于 1974 年获得诺贝尔奖。
“ 细胞自噬研究”是 2013 年诺贝尔生理学或医学奖预测的热门领域。
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Autophagy: target
Autophagic targets range in size and complexity
Individual long-lived macromolecules Whole organelles Microbial invaders
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Autophagy: purposes (a) quality control of disused or defunct
organelles such as irreversibly depolarized or leaky mitochondria;
(b) removal of toxic macromolecular aggregates too large for handling by smaller capacity or single-molecule-handling proteolytic systems of the cell (e.g. proteasome);
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Autophagy: purposes
(c) digestion of bulk cytoplasm expressly to replenish amino acids and energy during starvation or growth factor withdrawal;
(d) acting on or in concert with the molecular machineries and organelles at the interface between cell survival and cell death
(e) controlling and acting as an effector or a regulator of innate and adaptive immunity and inflammation,
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Autophagy: Function
The principal role of Autophagy this ubiquitous eukaryotic homeostatic mechanism is to ensure cell survival under adverse conditions
nutrient absence, growth factor withdrawal accumulation of toxic protein aggregates Faulty organelles (e.g., leaky mitochondria) infection by intracellular
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Autophagy Regulation Highly conserved and regulated process that maintains cellular
homeostasis and protects cells against starvation and microbe invasion
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Autophagy: Function
The physiologic and pathophysiologic roles of autophagy (and defects in autophagy) are vast, encompassing
Cancer Neurodegeneration metabolic diseases Aging Immunity.
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Autophagy
Autophagosome: A double membrane bound compartment that engulfs cytosol and degrades the cytoplasmic contents.
Large: 400-1500 nm
May originate from ER or from fusion of lipid-containing vesicles that form ‘sequestration crescent’.
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Autophagy : type
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Autophagy : type 根据自噬对底物的选择性可以将自噬可以分为
二类:选择性自噬和非选择性自噬。 非选择性自噬是指细胞内的细胞器随机运送到
溶酶体降解。 选择性自噬是指对降解的底物蛋白有专一性,
根据对底物蛋白选择性的不同,可以分为线粒体自噬,过氧化物体自噬、内质网自噬、核糖体自噬和细胞核的碎片状自噬等。
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细胞自噬途径
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Autophagy genes Based on S. cerevisiae yeast
studies.
ATG in yeast, homologs in other species.
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Three Stages
Initiation: nutrient starvation, growth factor-mediated starvation
Elongation Maturation
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Autophagy signaling
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Induction 外部因素 营养缺乏 激素 内部因素 细胞器损伤 异常成分积聚或必需成分存在 病原体
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酵母和哺乳动物中自噬诱导的调节
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酵母和哺乳动物中自噬诱导的调节
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Induction
Current Opinion in Immunology 2012, 24:21–31Current Opinion in Immunology 2012, 24:21–31
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Elongation Covalent linkage of Atg5 and Atg12
Covalent lipidation of Atg8
Enzymes Atg3, Atg7, and Atg10 are homologs of ubiquitylation enzymes but are used to modify pathway components instead of labeling them for degradation.
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Maturation GTPases (Rab24) mediate vesicle
fusion.
Intermediate autophagosomes Fuse with endosomal vesicles. Acquire LAMP, accumulate DAMP proteins.
Mature autolysosomes Fuse with lysosomes. Acquire cathepsins and acid phosphatases.
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The regulation of autophagy
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