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：
10214562
负责人：
HONG-GANG WANG
金额：
$ 34.85万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
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：
https://reporter.nih.gov/project-details/10214562
关键词：
Acute Myelocytic Leukemia Adaptor Signaling Protein Apoptosis Apoptotic Autophagocytosis Autophagosome Binding Proteins Biogenesis CASP8 and FADD-like apoptosis regulating protein CASP8 gene Caspase Cell Death Cell Survival Cells Cessation of life Childhood Acute Myeloid Leukemia Complex Data Death Domain Degradation Pathway Eating Gene Rearrangement Goals Hypoxia Impairment Lysosomes MLL gene Malignant Neoplasms Mammalian Cell Mediating Membrane Membrane Proteins Mixed-Lineage Leukemia Modeling Molecular Neoplasm Metastasis Nutrient Process Proteins Receptor Signaling Recycling Regulation Research Signal Transduction Starvation System Testing Therapeutic Vacuole Vesicle Yeasts anti-cancer aposome arm cancer cell cancer therapy clinically relevant environmental stressor improved in vivo in vivo Model inhibition of autophagy inhibitor/antagonist novel novel strategies recruit seal targeted cancer therapy trafficking tumor initiation tumorigenesis tumorigenic

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.

项目摘要/摘要该项目的目的是检验以下假设，即未成熟自噬体的积累膜诱导caspase-8的非传统激活将细胞保护自噬转化为凋亡用于新型的反癌策略。自噬是癌症的双刃剑，因为它可以抑制肿瘤发生或促进癌细胞存活。自噬通量缺乏选择性抑制剂已使它成为现实难以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了自噬体膜可以用作诱导细胞内死亡的信号复合物的平台（IDISC）激活caspase-8独立于死亡受体信号传导。从机械上讲，idisc的新兵双臂pro-caspase-8至自噬体膜：1）atg12-atg5：fadd：caspase-8; 2）LC3-II： P62：caspase-8。由于ATG12-ATG5在膜闭合并密封时从吞噬器中解离自噬小体流量流向溶酶体降解，我们假设抑制吞噬作用会闭合稳定IDISC组件以进行caspase-8激活。确实，我们的初步数据表明，细胞缺乏两个吞噬过程的调节剂ATG2A/B或VMP1累积了促进的未成熟吞噬作用 idisc介导的caspase-8激活。我们建议阐明吞噬作用的分子机制闭合将导致更有选择的自噬抑制目标，并为癌症提供新的机会治疗。我们将在以下特定目的中调查我们的假设：1）证明积累未成熟的吞噬流量引发了Idisc介导的caspase-8激活，并表征了分子调节剂非经典caspase-8激活； 2）测试ATG2A/B和VMP1调节吞噬的假设通过递送含ATG9的膜的封闭； 3）证明吞噬作用受损闭合可以在体内切换到idisc介导的凋亡，以抑制小儿急性髓样白血病（AML）具有MLL（混合谱系白血病）基因重排。