Non-canonical Caspase-8 Activation on Autophagosomal Membranes
自噬体膜上的非典型 Caspase-8 激活
基本信息
- 批准号:10448458
- 负责人:
- 金额:$ 34.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-01 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaAdaptor Signaling ProteinApoptosisApoptoticAutophagocytosisAutophagosomeBinding ProteinsBiogenesisCASP8 and FADD-like apoptosis regulating proteinCASP8 geneCaspaseCell DeathCell SurvivalCellsCessation of lifeChildhood Acute Myeloid LeukemiaComplexDataDeath DomainDegradation PathwayEatingGene RearrangementGoalsHypoxiaImpairmentLysosomesMLL geneMalignant NeoplasmsMammalian CellMediatingMembraneMembrane ProteinsMixed-Lineage LeukemiaModelingMolecularNeoplasm MetastasisNutrientProcessProteinsReceptor SignalingRecyclingRegulationResearchSignal TransductionStarvationSystemTestingTherapeuticVacuoleVesicleYeastsanti-canceraposomearmcancer cellcancer therapyclinically relevantenvironmental stressorimprovedin vivoin vivo Modelinhibition of autophagyinhibitornovelnovel strategiesrecruitsealtargeted cancer therapytraffickingtumor initiationtumorigenesistumorigenic
项目摘要
Project Summary/Abstract
The goal of this project is to test the hypothesis that an accumulation of immature autophagosomal
membranes induces the non-canonical activation of caspase-8 to switch cytoprotective autophagy to apoptosis
for a novel anti-cancer strategy. Autophagy is a double-edged sword in cancer as it can either suppress
oncogenesis or promote cancer cell survival. The lack of selective inhibitors of autophagic flux has made it
difficult to determine if inhibition of autophagy is a valid cancer strategy. We, and others, have demonstrated that
autophagosomal membranes can serve as platforms for an intracellular death-inducing signaling complex
(iDISC) that activates caspase-8 independent of death receptor signaling. Mechanistically, the iDISC recruits
pro-caspase-8 to autophagosomal membranes by two arms: 1) ATG12-ATG5: FADD: caspase-8; and 2) LC3-II:
p62: caspase-8. As ATG12-ATG5 dissociates from the phagophore upon membrane closure and sealed
autophagosomes traffic to lysosomes for degradation, we hypothesize that inhibition of phagophore closure will
stabilize iDISC assembly for caspase-8 activation. Indeed, our preliminary data reveal that cells deficient in
ATG2A/B or VMP1, two regulators of phagophore closure, accumulate immature phagophores that promote
iDISC-mediated caspase-8 activation. We propose that elucidation of the molecular mechanisms of phagophore
closure will lead to more selective targets for autophagy inhibition and present novel opportunities for cancer
therapy. We will investigate our hypothesis in the following specific aims: 1) to demonstrate that the accumulation
of immature phagophores initiates iDISC-mediated caspase-8 activation and characterize molecular regulators
of non-canonical caspase-8 activation; 2) to test the hypothesis that ATG2A/B and VMP1 regulate phagophore
closure through the delivery of ATG9-containing membranes; 3) to demonstrate that impaired phagophore
closure can switch autophagy to iDISC-mediated apoptosis in vivo for the suppression of pediatric acute myeloid
leukemia (AML) with MLL (mixed lineage leukemia) gene rearrangements.
项目总结/摘要
这个项目的目标是检验一个假设,即不成熟的自噬体的积累,
膜诱导caspase-8的非典型激活,将细胞保护性自噬转换为凋亡
一种新的抗癌策略。自噬在癌症中是一把双刃剑,因为它可以抑制
肿瘤发生或促进癌细胞存活。缺乏选择性的自噬流抑制剂,
很难确定抑制自噬是否是有效的癌症策略。我们和其他人已经证明,
自噬体膜可以作为细胞内死亡诱导信号复合物的平台
(iDISC),其独立于死亡受体信号传导而激活胱天蛋白酶-8。从机制上讲,iDISC招募
通过两个臂:1)ATG 12-ATG 5:FADD:胱天蛋白酶-8;和2)LC 3-II:
p62:半胱天冬酶-8。由于ATG 12-ATG 5在膜闭合时与吞噬细胞解离并密封,
自噬体运输到溶酶体进行降解,我们假设抑制吞噬细胞关闭将
稳定iDISC组装以活化半胱天冬酶-8。事实上,我们的初步数据显示,缺乏
ATG 2A/B或VMP 1是吞噬细胞关闭的两种调节剂,它们积累未成熟的吞噬细胞,
iDISC介导的caspase-8活化。我们建议阐明吞噬细胞的分子机制
关闭将导致更有选择性的自噬抑制靶点,并为癌症治疗提供新的机会。
疗法我们将研究我们的假设在以下具体目标:1)证明积累,
未成熟吞噬细胞的启动iDISC介导的caspase-8激活和表征分子调节剂
非典型caspase-8激活; 2)验证ATG 2 A/B和VMP 1调节吞噬细胞的假设
通过递送含ATG 9的膜封闭; 3)证明受损的吞噬细胞
闭合可以将自噬转换为iDISC介导的体内凋亡,以抑制小儿急性髓系白血病
白血病(AML)与MLL(混合谱系白血病)基因重排。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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HONG-GANG WANG的其他文献
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{{ truncateString('HONG-GANG WANG', 18)}}的其他基金
Autophagosome closure by the ESCRT machinery
通过 ESRT 机制封闭自噬体
- 批准号:
10383918 - 财政年份:2018
- 资助金额:
$ 34.14万 - 项目类别:
Autophagosome closure by the ESCRT machinery
通过 ESRT 机制封闭自噬体
- 批准号:
10132346 - 财政年份:2018
- 资助金额:
$ 34.14万 - 项目类别:
Non-canonical Caspase-8 Activation on Autophagosomal Membranes
自噬体膜上的非典型 Caspase-8 激活
- 批准号:
10214562 - 财政年份:2018
- 资助金额:
$ 34.14万 - 项目类别:
Non-canonical Caspase-8 Activation on Autophagosomal Membranes
自噬体膜上的非典型 Caspase-8 激活
- 批准号:
9983008 - 财政年份:2018
- 资助金额:
$ 34.14万 - 项目类别:
Autophagosome closure by the ESCRT machinery
通过 ESRT 机制封闭自噬体
- 批准号:
10703381 - 财政年份:2018
- 资助金额:
$ 34.14万 - 项目类别:
Autophagosome closure by the ESCRT machinery
通过 ESRT 机制封闭自噬体
- 批准号:
10453304 - 财政年份:2018
- 资助金额:
$ 34.14万 - 项目类别: