The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals
The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals
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DOI：
10.1016/j.immuni.2008.02.002
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发表时间：
2008-03-01
期刊：
影响因子：
32.4
通讯作者：
Ma, Averil
中科院分区：
文献类型：
--
作者：
Hitotsumatsu, Osamu;Ahmad, Regina-Celeste;Ma, Averil
胞壁酰二肽 (MDP) 是细菌细胞壁肽聚糖的产物，通过刺激含有 2 (NOD2) 的核苷酸结合寡聚结构域依赖性转录因子 NF kappa B 的激活和促炎基因的转录来激活先天免疫细胞。 A20 是一种泛素修饰酶，可限制肿瘤坏死因子 (TNF) 受体和 Toll 样受体 (TLR) 诱导的信号。我们现在证明 MDP 诱导初级巨噬细胞中受体相互作用蛋白 2 (RIP2) 的泛素化。 A20 缺陷细胞对 MDP 的反应显着增强，包括 RIP2 泛素化增加、NF kappa B 信号传导延长以及促炎细胞因子的产生增加。此外，在 A20 缺陷小鼠和携带 A20 缺陷造血细胞的嵌合小鼠中，对 MDP 的体内反应被夸大。这些夸张的反应独立于 TLR 接头 MyD88 和 TRIF 以及 TNF 信号而发生。这些发现表明 A20 在体外和体内直接限制 NOD2 诱导的信号，并为这些信号如何在生理上受到限制提供了新的见解。
Muramyl dipeptide (MDP), a product of bacterial cell-wall peptidoglycan, activates innate immune cells by stimulating nucleotide-binding oligomerization domain containing 2 (NOD2) -dependent activation of the transcription factor NF kappa B and transcription of proinflammatory genes. A20 is a ubiquitin-modifying enzyme that restricts tumor necrosis factor (TNF) receptor and Toll-like receptor (TLR) -induced signals. We now show that MDP induces ubiquitylation of receptor-interacting protein 2 (RIP2) in primary macrophages. A20-deficient cells exhibit dramatically amplified responses to MDP, including increased RIP2 ubiquitylation, prolonged NF kappa B signaling, and increased production of proinflammatory cytokines. In addition, in vivo responses to MDP are exaggerated in A20-deficient mice and in chimeric mice bearing A20-deficient hematopoietic cells. These exaggerated responses occur independently of the TLR adaptors MyD88 and TRIF as well as TNF signals. These findings indicate that A20 directly restricts NOD2 induced signals in vitro and in vivo, and provide new insights into how these signals are physiologically restricted.