AIM2はサイトゾリックdDNAを認識し,ASCと共にカスパース-1活性化炎症体を形成する
Veit Hornung1, Andrea Ablasser, Marie Charrel-Dennis
1Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. veit.hornung@uni-bonn.de
Nature
|January 23, 2009
まとめ
メラノーマ2 (AIM2) に存在しないタンパク質は,細胞質DNAのセンサーとして作用し,炎症反応を開始します. AIM2はASCと炎症体複合体を形成して,抗ウイルス免疫に不可欠なカスパゼ-1を活性化します.
科学分野:
- 免疫学 免疫学とは
- 分子生物学は分子生物学である.
- 細胞生物学 細胞生物学
背景:
- 生まれつきの免疫システムは,核酸を検出するために生殖系にコードされたパターン認識受容体を利用します.
- RNAセンサはよく特徴づけられているが,抗ウイルスおよび炎症反応を誘発する細胞質DNAセンサは,まだあまり理解されていない.
- 既知の経路には,I型インターフェロン誘導のためのTBK1-IRF3シグナル伝達と,IL1βおよびIL18処理のためのカスパース-1経由の炎症体活性化が含まれています.
研究 の 目的:
- 炎症シグナル伝達を開始する細胞塩基DNAのための新しい受容体を特定する.
- 細胞塩基DNAが炎症体活性化とカスパース-1媒介反応を誘発するメカニズムを解明する.
主な方法:
- マウスとヒトの細胞系を利用した.
- Aim2のノックダウンを使用して,DNAセンシングにおけるその役割を評価しました.
- AIM2,ASC,およびその他のシグナル伝達成分間のタンパク質とタンパク質の相互作用を調査した.
- 双鎖DNAとウイルス感染への反応として,カスパゼ-1の活性化を評価した.
主要な成果:
- メラノーマ2 (AIM2) の細胞塩基DNAの受容体として,PYHIN族のタンパク質であるAIM2に欠けることが確認されました.
- AIM2のHIN200ドメインがDNAと結合し,そのピリンドメインがASC.と相互作用することを示した.
- AIM2の活性化がNF-kappaBとcaspase-1の活性化につながることを示した.
- Aim2のノックダウンが,細胞質のdsDNAとワクチンウイルスへの反応としてカスパゼ-1の活性化を無効化することを確認しました.
結論:
- AIM2は,細胞質DNAの重要なセンサーとして機能します.
- AIM2は,そのDNAリガンドとASCとともに炎症体複合体を形成し,カスパース-1を活性化します.
- この経路は,カスパース-1によって媒介される炎症性および抗ウイルス反応の開始に不可欠です.
関連する概念動画
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...
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.
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.
Antigen Processing Pathways
MHC molecules are key players in the immune response, enabling T cells to recognize and respond to specific antigens. They are present on the surface of all nucleated cells in the body and are instrumental in presenting antigens to T cells and activating them. T cells recognize the MHC-antigen complex and initiate an immune response. MHC class I and MHC class II are two main types of MHC molecules, each associated with a distinct antigen processing pathway.
MHC Class I: Presenting Endogenous...
MHC Class I: Presenting Endogenous...


