AIM2 识别了细胞质的 dsDNA,并与 ASC 形成了 caspase-1 激活炎症体
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
概括
黑色素瘤2中缺少的蛋白质 (AIM2) 作为细胞质DNA的传感器,启动炎症反应. AIM2与ASC形成一个炎症酶复合体,以激活caspase-1,这对抗病毒免疫至关重要.
科学领域:
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
背景情况:
- 天生的免疫系统利用生殖系编码的模式识别受体来检测核酸.
- 虽然RNA传感器的特征很好,但触发抗病毒和炎症反应的细胞质DNA传感器仍然不太了解.
- 已知的途径包括TBK1-IRF3信号传递用于I型干扰素诱导和通过IL1beta和IL18处理的caspase-1通过炎症酶激活.
研究的目的:
- 为了识别引发炎症信号的细胞质DNA的新型受体.
- 阐明细胞质DNA触发炎酶激活和卡斯帕酶-1介导反应的机制.
主要方法:
- 使用了老鼠和人类细胞系.
- 使用Aim2的淘汰来评估其在DNA传感中的作用.
- 研究了AIM2,ASC和其他信号组件之间的蛋白质-蛋白质相互作用.
- 评估了对双链DNA和病毒感染的反应中的caspase-1激活.
主要成果:
- 在黑色素瘤2 (AIM2) 中缺席,这是PYHIN家族蛋白质,作为细胞核DNA的受体.
- 证明了AIM2的HIN200域与DNA结合,而它的pyrin域与ASC相互作用.
- 表明AIM2的激活导致NF-kappaB和caspase-1的激活.
- 证实Aim2敲击取消了对细胞质dDNA和疫苗病毒的反应中的caspase-1激活.
结论:
- AIM2作为细胞质DNA的关键传感器.
- AIM2与其DNA连接体和ASC形成一个炎症酶复合体,以激活caspase-1.
- 这一途径对于启动由caspase-1介导的炎症和抗病毒反应至关重要.
相关概念视频
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...


