Activation of PAD4 in NET formation.
Activation of PAD4 in NET formation.
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DOI：
10.3389/fimmu.2012.00360
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发表时间：
2012
影响因子：
7.3
通讯作者：
Mowen KA
中科院分区：
文献类型：
--
作者：
Rohrbach AS;Slade DJ;Thompson PR;Mowen KA
肽基精氨酸脱亚氨酶（PADs）将多种蛋白质底物中的精氨酸残基转化为非核糖体编码的氨基酸瓜氨酸。PAD4在粒细胞中表达，并通过PAD4介导的组蛋白瓜氨酸酶对中性粒细胞胞外陷阱（NET）的形成至关重要。组蛋白的瓜氨酸被认为通过诱导染色质去凝聚和促进被抗菌分子包被的染色体DNA的排出来促进NET形成。已经报道了许多刺激导致PAD4激活和NET形成。然而，这个信号传导过程如何进行以及PAD4如何在细胞中被激活在很大程度上是未知的。在这里，我们描述了各种刺激和信号通路，已牵连在PAD4激活和NET的形成，包括活性氧的产生的作用。为了为上述讨论提供基础，我们首先描述了PAD 4的结构和功能，以及这些研究如何导致PAD特异性抑制剂的开发。对调节PAD 4激活的受体和信号通路的全面调查对于我们理解先天免疫将是重要的，并且PAD 4激活中的信号中间体的鉴定也可能导致靶向NET相关发病机制的药物的产生。
Peptidylarginine deiminases, or PADs, convert arginine residues to the non-ribosomally encoded amino acid citrulline in a variety of protein substrates. PAD4 is expressed in granulocytes and is essential for the formation of neutrophil extracellular traps (NETs) via PAD4-mediated histone citrullination. Citrullination of histones is thought to promote NET formation by inducing chromatin decondensation and facilitating the expulsion of chromosomal DNA that is coated with antimicrobial molecules. Numerous stimuli have been reported to lead to PAD4 activation and NET formation. However, how this signaling process proceeds and how PAD4 becomes activated in cells is largely unknown. Herein, we describe the various stimuli and signaling pathways that have been implicated in PAD4 activation and NET formation, including the role of reactive oxygen species generation. To provide a foundation for the above discussion, we first describe PAD4 structure and function, and how these studies led to the development of PAD-specific inhibitors. A comprehensive survey of the receptors and signaling pathways that regulate PAD4 activation will be important for our understanding of innate immunity, and the identification of signaling intermediates in PAD4 activation may also lead to the generation of pharmaceuticals to target NET-related pathogenesis.