相关实验视频
Updated: Jul 16, 2026

08:35
Examining BCL-2 Family Function with Large Unilamellar Vesicles
Published on: October 5, 2012
收回: 亲细胞 BAX 和 BAK 通过与 IRE1alpha 直接相互作用来调节未折叠的蛋白质反应
Claudio Hetz1, Paula Bernasconi, Jill Fisher
1Howard Hughes Medical Institute, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA 02115, USA. chetz@hsph.harvard.edu
概括
亲细胞蛋白BAX和BAK对于激活未折叠蛋白质响应 (UPR) 信号通路至关重要. 它们的缺失会损害内等离子体网膜的应激反应,导致小鼠的肝损伤.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 压力反应 应激反应
背景情况:
- 错误折叠的蛋白质积聚在内质网膜 (ER) 中,启动了未折叠的蛋白质反应 (UPR).
- UPR主要由需要内醇的酶-1alpha (IRE1alpha),ER跨膜激酶和内核酶进行介导.
- 在UPR信号传递中亡蛋白的作用仍然不完全理解.
研究的目的:
- 调查BAX和BAK在UPR信号传输中的作用.
- 检查BAX和BAK缺失对ER应激反应在体内和体外的影响.
- 阐明将亡途径与UPR联系起来的分子机制.
主要方法:
- 使用BAX和BAK双淘汰赛 (DKO) 鼠标模型.
- 在DKO小鼠和对照 littermates中使用tunicamycin诱导ER压力.
- 分析了UPR信号组件,包括IRE1alpha基质X盒结合蛋白1 (XBP1) 和其向基因.
- 在ER压力细胞中研究了BAX/BAK和IRE1alpha之间的蛋白质复合体形成.
主要成果:
- DKO小鼠对尼卡米辛诱导的ER压力表现出异常反应,其特征是严重的肝损伤.
- 在ER压力下的DKO细胞显示出缺陷的IRE1alpha信号.
- 在DKO小鼠中,IRE1alpha基底XBP1及其下游目标基因的表达显著下降.
- 发现BAX和BAK与IRE1alpha的细胞质域形成蛋白质复合体,这对其激活至关重要.
结论:
- BAX和BAK对于激活IRE1alpha介导的UPR信号来说至关重要.
- 这些预亡蛋白在ER膜上起作用,将核心亡途径与UPR连接起来.
- 缺少BAX和BAK会损害对ER压力的适应性反应,导致细胞和组织损伤.
相关概念视频
Restarting Stalled Replication Forks
DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart, a...
ER Retrieval Pathway
In the secretory pathway, vesicles transport proteins from one cellular compartment to another in forward transport to deliver the protein to its correct location. Occasionally, misfolded proteins and incorrect proteins escape their original compartments, and a retrieval pathway is used to return the escaped proteins to their original compartment.
The ER uses many checkpoints to prevent the entry of incorrectly folded or a resident protein as cargo onto a transport vesicle. These mechanisms...
The ER uses many checkpoints to prevent the entry of incorrectly folded or a resident protein as cargo onto a transport vesicle. These mechanisms...
The Unfolded Protein Response
The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
Regulation of the Unfolded Protein Response
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
The Intrinsic Apoptotic Pathway
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
Cellular Injury V: Apoptosis and Autophagy
Cells respond to damage and stress through highly coordinated processes that decide whether they survive or undergo controlled self-destruction. Two major pathways involved in this regulation are apoptosis, a type of programmed cell death, and autophagy, a survival mechanism that helps cells adapt to adverse conditions.ApoptosisApoptosis removes aged or injured cells to maintain tissue balance. During this process, the cell shrinks, chromatin condenses and fragments, and membrane-bound...

