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Autophagy and Immunity
Jianzhong Chen
Institute of Immunology
Zhejiang University School of Medicine
Nov 1, 2013
Autophagy
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。
发现
发现
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比利时科学家Christian de Duve在上世纪50
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
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Autophagic targets range in size and complexity
Individual long-lived macromolecules
Whole organelles
Microbial invaders
Autophagy: purposes
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(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
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(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
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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
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The physiologic and pathophysiologic roles of
autophagy (and defects in autophagy) are vast,
encompassing
Cancer
Neurodegeneration
metabolic diseases
Aging
Immunity.
Autophagy


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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
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Based on S. cerevisiae yeast studies.
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ATG in yeast, homologs in other species.
Three Stages
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Initiation: nutrient starvation,
growth factor-mediated starvation
Elongation
Maturation
Autophagy signaling
Induction
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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, 24:21–31
Elongation
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Covalent linkage of Atg5 and Atg12
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Covalent lipidation of Atg8
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Enzymes Atg3, Atg7, and Atg10 are
homologs of ubiquitylation enzymes but
are used to modify pathway
components instead of labeling them
for degradation.
Maturation
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GTPases (Rab24) mediate vesicle fusion.
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Intermediate autophagosomes
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Fuse with endosomal vesicles.
Acquire LAMP, accumulate DAMP proteins.
Mature autolysosomes
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Fuse with lysosomes.
Acquire cathepsins and acid phosphatases.
The regulation of autophagy
Autophagy Regulation
Autophagy is regulated by nutrients, growth factors and stress.
Various forms of autophagy induction
Tuberculosis 92 (2012) 388e396
Regulation of autophagy by cytokines
Cellular Signalling 25 (2013) 1272–1278
Detection methods
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Microscopy
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Biochemistry
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Electron microscopy – ultrastructure,
morphology, volumetrics, staining.
Enzyme activity assays.
Radioactive degradation studies.
Marker studies
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Autophagosomal or organelle markers.
Fluorescence or immunodetection.
Autophagy and diseases
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Oncology
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Liver
 Breast
 Colon
 Lung
Beclin-1
Myodegerative
disease
 Cardiac stress
 a-antitrypsin
deficiency
……
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Brain
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Alzheimer
Multiple Sclerosis
Parkinson’s
disease
Hungtingdon’s
disease
Miscellaneous
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Cellular Process
Apoptosis
 Aging
 Growth
……
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Autophagy and immunity
Antigen presentation
 TLR signaling
 Infection
 Inflammation
……
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Role of autophagy
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Does autophagy benefit the host as a
defense mechanism?
Does autophagy benefit the microbe by
facilitating survival and replication?
Or both?
Pharmacological Research 66 (2012)
475– 483
PRRs inflammasomes and autophagy
Current Opinion in Immunology 2012, 24:21–31
Exp. Mol. Med. 44(2), 99-108, 2012
Manipulation of autophagy by intracellular bacteria
Science,2013,340:697
Human macrophage host defense mechanisms
against intracellular M. tuberculosis.
Current Opinion in Immunology 2008, 20:371–376
M. tuberculosis inhibits phagosome-lysosome fusion
Tuberculosis 92 (2012) 388e396
The role of autophagy in the mode of action of cytokines and antituberculosis drugs in M. tuberculosis infection.
Cytokine & Growth Factor Reviews 24 (2013) 335–343
Autophagy as a mechanism to
prevent exaggerated
endotoxin-induced IL-1β
production in macrophages.
TIP OF THE
ICEBERG?