基于库林3的多比基化和p62依赖的caspase-8聚合介导了外源性亡信号
Zhaoyu Jin1, Yun Li, Robert Pitti
1Department of Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Cell
|May 12, 2009
概括
死亡受体的激活会触发caspase-8的多比基因化和聚合,从而增强亡. 这一过程涉及CUL3 E3结合酶和p62,导致细胞死亡承诺.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- 细胞表面死亡受体 (DR4,DR5) 通过DISC形成启动细胞亡.
- 亡的承诺取决于caspase-8的激活和释放,但完全的激活机制仍然不清楚.
研究的目的:
- 阐明控制酶-8激活和亡承诺的分子机制.
主要方法:
- 在死亡受体结合后研究了caspase-8的多比基因化和聚合.
- 利用技术来识别相互作用的E3连接酶和二维基基因酶.
- 研究了p62在caspase-8聚合和激活中的作用.
主要成果:
- 发现死亡受体结合会通过一种新的基于CUL3的E3结合酶与DISC的相互作用诱导caspase-8的多比基化.
- RBX1对于CUL3介导的多基化是必不可少的,而A20则逆转了它.
- p62促进了多基化酶-8的聚合,驱动其完全激活和致力于细胞死亡.
结论:
- 确定了一种新的多比基因化和聚合依赖的机制,用于积极控制亡信号.
- 卡斯帕斯-8多比基因化和随后的聚合对于有效启动亡至关重要.
相关概念视频
Regulated Protein Degradation
It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
Apoptosis
Apoptosis is a combination of two Greek words, 'apo' and 'ptosis,' meaning separation and falling off, respectively. Hippocrates used this word to describe gangrene, which was caused due to bandaging of fractured bones. Apoptosis was distinguished from necrosis in 1970 when John Kerr reported observations of morphological changes occurring during apoptosis. During one experiment, he observed that the disruption of blood supply to the liver tissue resulted in a size reduction of the tissue.
Caspases
Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside cells.
The Extrinsic Apoptotic Pathway
The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
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...
Phagocytosis of Apoptotic Cells
Cells undergoing apoptosis form apoptotic bodies that must be removed immediately to prevent inflammation, autoimmune diseases, and necrosis. Phagocytosis is carried out by professional phagocytes such as macrophages or immature dendritic cells. Non-professional phagocytes such as epithelial cells and fibroblasts also take part in this process; however, they are not as effective as professional phagocytes.
Normal cells contain receptors that prevent them from being recognized by phagocytes.
Normal cells contain receptors that prevent them from being recognized by phagocytes.


