Mechanism of Bax/Bak Activation During Apoptosis

细胞凋亡过程中 Bax/Bak 激活的机制

• 批准号: 10004152
• 负责人: Xu Luo
• 金额: $ 32.03万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004152
• 关键词: Apoptosis; Apoptotic; Autoimmune Diseases; BCL-2 Protein; BCL2 gene; Bax protein; Biochemical; Cell Death; Cell physiology; Cells; Cellular biology; Cessation of life; Consensus; Data; Defect; Development; Disease; Ensure; Family; Genetic; Goals; Homeostasis; In Vitro; Interruption; Kinetics; Knock-out; Life; Lipids; MCL1 gene; Malignant Neoplasms; Mediating; Membrane; Mitochondria; Modeling; Molecular; Mutagenesis; Nerve Degeneration; Outer Mitochondrial Membrane; Pathologic; Pathway interactions; Play; Process; Protein Family; Protein p53; Proteins; Puma; Regulation; Research; Role; Signal Pathway; Stimulus; Structure; Subgroup; Testing; Therapeutic Intervention; Work; base; cancer cell; experimental study; genome editing; human disease; insight; member; new therapeutic target; novel; programs; targeted treatment; tool

Apoptosis is an essential cellular death program that controls proper development and maintains homeostasis. Aberrant regulation of apoptosis contributes to many diseases, such as neurodegeneration, autoimmune diseases, and cancer. The mitochondria-dependent pathway is a major apoptotic pathway, and is primarily regulated and executed by the Bcl-2 family proteins. The Bcl-2 family includes five anti-apoptotic members, two effector proteins Bax and Bak, and eight pro-apoptotic BH3-only proteins. They control the mitochondrial pathway at the step of mitochondrial outer membrane permeabilization (MOMP), a central control point leading to apoptosis. Our long term goal is to elucidate the signaling pathways and molecular mechanisms responsible for mitochondria-dependent apoptosis, and provide positive impact on the development of more potent and specific therapies against apoptosis-related diseases. While genetic and biochemical studies have long established the role of Bax and Bak as two essential effectors of MOMP, the mechanism of Bax/Bak activation, commonly considered the life-to-death switch of the cells, has been intensively investigated in the past two decades. The current consensus is that while all pro-apoptotic BH3-only proteins suppress the anti- apoptotic Bcl-2 proteins, a subset of BH3-only proteins directly engage and activate Bax and Bak during apoptosis. However, in our preliminary studies, we provide genetic evidence suggesting that such a BH3-only protein-mediated direct activation is not necessary for Bax/Bak activation and apoptosis. Instead, our results suggest that upon the BH3-only protein-mediated neutralization of the anti-apoptotic Bcl-2 proteins, Bax/Bak undergo a membrane-dependent, spontaneous activation process. Based on our preliminary studies, we propose a new model of Bax/Bak activation, which will be examined primarily by genetics, cell biology, and biochemical approaches. The following three Aims are proposed. In Aim 1, we will examine the role of the BH3-only proteins and other potential direct activators in Bax/Bak activation following the inactivation of anti- apoptotic Bcl-2 proteins. In Aim 2, we will investigate the involvement of mitochondrial outer membrane in the regulation of Bax/Bak activation. In Aim 3, we will investigate the mechanism of anti-apoptotic Bcl-2 protein- mediated suppression of the Bax/Bak activation. Overall, our proposed studies are expected to elucidate the mechanism of Bax/Bak activation during apoptosis. This proposal may not only unravel one of the long standing mysteries in apoptosis research, but also provide novel targets for therapeutic intervention.

凋亡是一个必不可少的细胞死亡计划，可控制正常发育并维持稳态。 凋亡的异常调节会导致许多疾病，例如神经变性，自身免疫性 疾病和癌症。线粒体依赖性途径是主要的凋亡途径，主要是 由BCL-2家族蛋白进行调节和执行。 Bcl-2家族包括五个抗凋亡成员，两个 效应蛋白BAX和BAK，以及八个仅凋亡BH3蛋白。他们控制线粒体 线粒体外膜通透性（MOMP）的途径，中心控制点的前进点 凋亡。我们的长期目标是阐明信号通路和分子机制 负责线粒体依赖性细胞凋亡，并对更多的发展产生积极影响 针对凋亡相关疾病的有效和特定疗法。而遗传和生化研究具有 长期以来，Bax和Bak的作用是MOMP的两个基本效应子，即Bax/Bak的机制 普遍认为细胞生命转换的激活已在 过去二十年。目前的共识是，虽然所有促凋亡BH3的蛋白质都抑制了抗 - 凋亡Bcl-2蛋白，仅BH3蛋白的一部分直接参与并激活Bax和Bak 凋亡。但是，在我们的初步研究中，我们提供了遗传证据，表明这种仅BH3 蛋白质介导的直接激活对于Bax/Bak激活和凋亡是不需要的。相反，我们的结果 建议在仅BH3蛋白介导的抗凋亡Bcl-2蛋白的中和BAX/BAK中和中和 经历依赖膜的自发激活过程。根据我们的初步研究，我们 提出了一种新的Bax/Bak激活模型，该模型将主要通过遗传学，细胞生物学和 生化方法。提出了以下三个目标。在AIM 1中，我们将研究 抗抗活化后，仅BH3蛋白和其他潜在的直接激活剂在BAX/BAK激活中 凋亡Bcl-2蛋白。在AIM 2中，我们将研究线粒体外膜的参与 BAX/BAK激活的调节。在AIM 3中，我们将研究抗凋亡Bcl-2蛋白的机理 介导的BAX/BAK激活的抑制。总体而言，我们提出的研究有望阐明 凋亡过程中Bax/Bak激活的机制。该提议不仅可以揭开长期的一个 细胞凋亡研究中的谜团，但也为治疗干预提供了新的目标。

项目成果

Hexokinases inhibit death receptor-dependent apoptosis on the mitochondria.

• DOI: 10.1073/pnas.2021175118
• 发表时间: 2021-08-17
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Lauterwasser J;Fimm-Todt F;Oelgeklaus A;Schreiner A;Funk K;Falquez-Medina H;Klesse R;Jahreis G;Zerbes RM;O'Neill K;van der Laan M;Luo X;Edlich F
• 通讯作者: Edlich F