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.

细胞凋亡是控制正常发育和维持体内平衡的重要细胞死亡程序。 细胞凋亡的异常调节会导致许多疾病，例如神经退行性疾病、自身免疫性疾病 疾病和癌症。线粒体依赖性途径是主要的细胞凋亡途径，并且主要是 由 Bcl-2 家族蛋白调节和执行。 Bcl-2家族包括五个抗凋亡成员，两个 效应蛋白 Bax 和 Bak，以及八种促凋亡 BH3 蛋白。它们控制线粒体 线粒体外膜透化（MOMP）步骤中的途径，是导致线粒体外膜透化的中央控制点 至细胞凋亡。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，并对更多细胞的发育产生积极影响 针对细胞凋亡相关疾病的有效且特异性的疗法。虽然遗传和生化研究已经 长期以来确立了Bax和Bak作为MOMP的两个重要效应器的作用，Bax/Bak的机制 激活通常被认为是细胞的生死转换，已在 过去二十年。目前的共识是，虽然所有促凋亡 BH3 蛋白都会抑制抗凋亡蛋白 凋亡 Bcl-2 蛋白是仅 BH3 蛋白的一个子集，在凋亡过程中直接参与并激活 Bax 和 Bak 细胞凋亡。然而，在我们的初步研究中，我们提供了遗传证据表明这种仅 BH3 Bax/Bak 激活和细胞凋亡不需要蛋白质介导的直接激活。相反，我们的结果 表明仅 BH3 蛋白介导的抗凋亡 Bcl-2 蛋白的中和作用，Bax/Bak 经历膜依赖性自发激活过程。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。提出以下三个目标。在目标 1 中，我们将研究 BH3-only 蛋白和其他潜在的直接激活剂在抗-Bax/Bak 失活后激活 凋亡 Bcl-2 蛋白。在目标 2 中，我们将研究线粒体外膜在 Bax/Bak 激活的调节。在目标3中，我们将研究Bcl-2蛋白的抗凋亡机制—— 介导的 Bax/Bak 激活抑制。总的来说，我们提出的研究预计将阐明 细胞凋亡过程中 Bax/Bak 激活的机制这一提议不仅可能解开长期存在的问题之一 细胞凋亡研究中长期存在的谜团，但也为治疗干预提供了新的靶点。

项目成果

MARCH5-dependent degradation of MCL1/NOXA complexes defines susceptibility to antimitotic drug treatment.

MCL1/NOXA 复合物的 MARCH5 依赖性降解决定了抗有丝分裂药物治疗的敏感性。

• 发表时间: 2020-08
• 影响因子: 12.4
• 作者: Haschka, Manuel D;Karbon, Gerlinde;Soratroi, Claudia;O'Neill, Katelyn L;Luo, Xu;Villunger, Andreas
• 通讯作者: Villunger, Andreas

Venetoclax causes metabolic reprogramming independent of BCL-2 inhibition.

Venetoclax 可引起独立于 BCL-2 抑制的代谢重编程。

• 发表时间: 2020
• 影响因子: 9
• 作者: Roca;Rodriguez;Sumpton, David;Cloix, Catherine;Mullin, Margaret;Mackay, Gillian M;O'Neill, Katelyn;Lemgruber, Leandro;Luo, Xu;Tait, Stephen W G
• 通讯作者: Tait, Stephen W G

Hexokinases inhibit death receptor-dependent apoptosis on the mitochondria.

己糖激酶抑制线粒体上死亡受体依赖性细胞凋亡。

• 发表时间: 2021
• 影响因子: 11.1
• 作者: Lauterwasser, Joachim;Fimm;Oelgeklaus, Aline;Schreiner, Annabell;Funk, Kathrin;Falquez;Klesse, Ramona;Jahreis, Günther;Zerbes, Ralf M;O'Neill, Katelyn;van der Laan, Martin;Luo, Xu;Edlich, Frank
• 通讯作者: Edlich, Frank