カルリン3基のポリユビキチン化と,カスパース8のp62依存的結合は,外来アポトーシスシグナル伝達を媒介する
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
まとめ
死亡受容体の活性化は,カスパース-8のポリユビキチン化と集積を誘発し,アポトーシスを強化します. このプロセスには,CUL3 E3リガゼとp62が含まれ,細胞死へのコミットメントにつながります.
科学分野:
- 細胞生物学 細胞生物学
- 分子生物学は分子生物学である.
- バイオケミストリー バイオケミストリー
背景:
- 細胞表面死受容体 (DR4,DR5) は,DISC形成経由でアポトーシスを開始する.
- アポトーシスの関与は,カスパース-8の活性化と放出に依存するが,完全な活性化メカニズムは不明である.
研究 の 目的:
- カスパゼ8の活性化とアポトーシスの関与を制御する分子機構を解明する.
主な方法:
- 死亡受容体結合後のカスパース-8のポリユビキチン化と集積を調査した.
- 相互作用するE3リガゼとデウビキキチナゼを特定する技術を用いた.
- カスパース-8の結合と活性化におけるp62の役割を調べました.
主要な成果:
- 死亡受容体結合が,新しいCUL3ベースのE3リガース相互作用を通じてカスパース-8ポリユビキチネーションを誘導することを発見しました.
- RBX1はCUL3媒介のポリユビキチン化に不可欠であり,A20はそれを逆転させた.
- p62は,ポリユビキチン化カスパース-8の結合を促進し,その完全な活性化と細胞死へのコミットメントを促した.
結論:
- アポプトーシスシグナル伝達の陽性制御のための新しいポリユビキチン化および集積依存メカニズムを特定しました.
- カスパース-8のポリユビキチン化と,その後の集積は,効率的なアポトーシス開始に不可欠である.
関連する概念動画
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.


