Enigma of Inflammasome Activation by Kinases.
Enigma of Inflammasome Activation by Kinases.
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DOI：
10.1161/atvbaha.119.312965
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发表时间：
2019-07
期刊：
影响因子：
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通讯作者：
Ying H. Shen;J. Abe
中科院分区：
文献类型：
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作者：
Ying H. Shen;J. Abe
炎症体是由信号传感平台蛋白(如NLRP3[NOD-、LRR(富含亮氨酸重复序列)-和PYRIN结构域包含3]、AIM2[黑色素瘤2中缺失]和NLRC4[NLR(节点样受体)家族卡片(caspase激活和募集结构域包含4])、接头蛋白ASC(包含一个卡片的凋亡相关斑点样蛋白)和效应蛋白caspase-1]组成的大型多蛋白质复合体。这些复合体作为信号平台激活caspase-1，caspase-1进而裂解和处理炎性细胞因子，如IL(IL)-1β和IL-18，并触发炎症反应。活化的caspase-1还裂解成孔蛋白Gasdermin D，产生氨基末端片段，该片段寡聚并在质膜上形成膜孔，导致钾外流和下垂。随后的钾外流导致NLRP3进一步激活。1通过诱导强烈的炎症反应和嗜酸性细胞死亡，炎症体级联在包括动脉粥样硬化在内的许多心血管疾病中促进组织炎症和破坏。因此，更好地了解炎性小体的调节和识别负责炎性小体激活的分子对于开发有效的治疗方法来治疗那些炎性小体激活至关重要的疾病至关重要。
Inflammasomes are large multiprotein complexes composed of signal sensing platform proteins (eg, NLRP3 [NOD-, LRR (leucine-rich repeat)-, and pyrin domaincontaining 3], AIM2 [absent in melanoma 2], and NLRC4 [NLR (NOD-like receptor) family CARD (caspase activation and recruitment domain) domain containing 4]), adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD), and effector protein caspase-1. These complexes serve as signaling platforms that activate caspase-1, which in turn cleaves and processes inflammatory cytokines such as IL (interleukin)-1β and IL-18 and triggers the inflammatory response. Active caspase-1 also cleaves the pore-forming protein gasdermin D and generates the aminoterminal fragment, which oligomerizes and forms membrane pores in the plasma membrane, resulting in potassium efflux and pyroptosis. The subsequent potassium efflux leads to further NLRP3 activation.1 By inducing the robust inflammatory response and pyroptotic cell death, the inflammasome cascade contributes to tissue inflammation and destruction in many cardiovascular diseases including atherosclerosis. Thus, better understanding of the regulation of inflammasome and identification of the molecules responsible for inflammasome activation are critical for developing effective therapies to treat diseases in which activation of inflammasome is critically involved.