autophagy and immunity jianzhong chen institute of immunology zhejiang university school of medicine...

Autophagy and Immunity

Jianzhong Chen

Institute of ImmunologyZhejiang University School of Medicine

Nov 1, 2013

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

发现

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。

Autophagy: target

Autophagic targets range in size and complexity

Individual long-lived macromolecules Whole organelles Microbial invaders

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);

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,

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

Autophagy Regulation Highly conserved and regulated process that maintains cellular

homeostasis and protects cells against starvation and microbe invasion

Autophagy: Function

The physiologic and pathophysiologic roles of autophagy (and defects in autophagy) are vast, encompassing

Cancer Neurodegeneration metabolic diseases Aging Immunity.

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’.

Autophagy ： type

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。

细胞自噬途径

Autophagy genes Based on S. cerevisiae yeast

studies.

ATG in yeast, homologs in other species.

Three Stages

Initiation: nutrient starvation, growth factor-mediated starvation

Elongation Maturation

Autophagy signaling

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

酵母和哺乳动物中自噬诱导的调节

酵母和哺乳动物中自噬诱导的调节

Induction

Current Opinion in Immunology 2012, 24:21–31Current Opinion in Immunology 2012, 24:21–31

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.

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.

The regulation of autophagy