Post on 17-Jan-2016
Autophagy: regulation and crosstalk with apoptosis
Tianfeng Lan
IMI CONFIDENTIAL www.xianimi.com 2
Overview
(1) de novo formation of a double-membrane bound structure or phagophore
(2) elongation of this lipid-based membrane
(3) Encapsulation(包裹) of intracellular cargo to form the mature autophagosome
An ancient process that is highly conserved among eukaryotes
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Core MachineryMTOR ( mechanistic target of rapamycin)
MTOR is active in nutrient-rich conditions, inhibiting autophagy and protein degradation. When MTOR is inactivated by starvation conditions, dephosphorylated ULK1 dissociates from the MTOR complex and phosphorylates ATG13 and RB1CC1/FIP200
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The PtdIns3K complex is assembled at the site of the nascent autophagosomal membrane. UVRAG and ATG14 are found in BECN1 complexes in a mutually exclusive manner
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The two ubiquitin-like conjugation systems essential for membrane
elongation are outlined schematically.
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The autophagosomal membrane (orange crescent) is studded with LC3–PE (stylized in black). The membrane elongation is dependent on the ATG12–ATG5-ATG16L1 conjugation system
Sources of Autophagosomal Membranes
Sources Evidences
endoplasmic reticulum immunostaining(PI3K, ATG14), electron microscopy
mitochondria flourescence microscopy(LC3, ATG5)
Golgi apparatus ATG9
plasma membrane PM SNAREs
Induction of autophay
nutrient status
hormonal regulation
hypoxia
heat sress
ROS
ER stress
UPR :unfold protein response
ATF6, ERN1/IRE1, EIF2AK3/PERK pathway
Autophagy
Types of Autophagy
Aggrephagy(聚集吞噬 )
Degrading proteins that are assembled into large protein aggregates
Aggresome requires K63 linked polyubiquitination to recruit autophagy receptors SQSTM1, NBR1 and WDFY3. These receptors provide a physical link to ATG8
Allophagy, crinophagy and zymophagy
Allophagy: degradation of paternally-derived mitochondriaupon fertilization in the zygote
Crinophagy(分泌吞噬) :secretory granules containing hormones are directly routed to lysosomes without contribution from autophagy
zymophagy(酶原吞噬 ):degradation of activated zymogen granules
Exophagy(分泌吞噬)
Nondegradative processes involved in protein secretion: IL-6, IL-8
Heterophagy and endosomal microautophagy
Heterophagy(异体吞噬 ): degradation extracellular material that has been internalized within the cell
Immunophagy(免疫吞噬 )
Type I: processing of foreign or endogenous immunologically active molecules. xenophagy, the autophagic activation of macrophages, pattern recognition receptor activation, MHC class II endogenous antigen presentation, and thymic selection
Type II: regulates cell viability and immune cell function. Specific roles for this type include: T/B cell homeostasis, T cell maturation and Paneth cell maintenance
Type III immunophagy utilizes specific ATG proteins to regulate immune signaling
Lipophagy(脂质吞噬 )the metabolic regulation of lipids through degradation of lipid dropl
ets (LDs) by autophagy
Mitophagy(线粒体自噬 )
Selective degradation of mitochondria through autophagy, although the process may be cell specific within mammals.
Nucleophagy(胞核自噬 )
mammalian cells can exhibit complete encapsulation of the nucleus
Pexophagy(过氧化物酶体自噬)selective degradation of peroxisomes through autophagy
Reticulophagy and ribophagy
Degradation of the ER through reticulophagy occurs in response to ER stress
Ribophagy, the selective elimination of free ribosomes in the cytosol, is also linked to the ER stress response similar to reticulophagy.
Xenophagy(异物自噬 )
Viruses, bacteria and parasites can be eliminatedin an autophagic process involved in innate immunity defense
termed xenophagy
Autophagy–Apoptosis Crosstalk
BECN1–BCL2 interaction
BCL2 acts as a BECN1 antagonist, through direct interaction with the BH3 domain found on BECN1, preventing activation of the PtdIns3K complex and induction of autophagy
BECN1–BCL2L11 interaction
Inactive BCL2L11 may act to repress BECN1 until autophagy is induced by nutrient deprivation
案例分析
拓步雄,中文,设计到撰写修改时间约 1周,首次投稿《中华高血压杂志》
修改意见较多,且非常注意实验的细节
二次修回,依然在抠细节!
退稿!
1.尊重服从专家审稿意见!
2.中华类文章对于实验方法,如分组,分组依据,处理时间要求较严格!
3.如果不明白编辑的意图,可以电话询问!