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首页> 外文期刊>Nature immunology >Two distinct ubiquitin-binding motifs in A20 mediate its anti-inflammatory and cell-protective activities
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Two distinct ubiquitin-binding motifs in A20 mediate its anti-inflammatory and cell-protective activities

机译：A20中的两个不同的泛素结合基序介导其抗炎和细胞保护活性

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Protein ubiquitination regulates protein stability and modulates the composition of signaling complexes. A20 is a negative regulator of inflammatory signaling, but the molecular mechanisms involved are ill understood. Here, we generated Tnfaip3 gene-targeted A20 mutant mice bearing inactivating mutations in the zinc finger 7 (ZnF7) and ZnF4 ubiquitin-binding domains, revealing that binding to polyubiquitin is essential for A20 to suppress inflammatory disease. We demonstrate that a functional ZnF7 domain was required for recruiting A20 to the tumor necrosis factor receptor 1 (TNFR1) signaling complex and to suppress inflammatory signaling and cell death. The combined inactivation of ZnF4 and ZnF7 phenocopied the postnatal lethality and severe multiorgan inflammation of A20-deficient mice. Conditional tissue-specific expression of mutant A20 further revealed the key role of ubiquitin-binding in myeloid and intestinal epithelial cells. Collectively, these results demonstrate that the anti-inflammatory and cytoprotective functions of A20 are largely dependent on its ubiquitin-binding properties.
机译：蛋白质泛素调节蛋白质稳定性并调节信号配合物的组成。 A20是炎症信号传导的负调节因子，但涉及的分子机制均已理解。这里，我们产生的TNFAIP3基因靶向A20突变小鼠携带锌指7（ZnF7）和ZnF4遍突蛋白结合结构域的灭活突变，揭示与络合蛋白的结合对于A20是必不可少的抑制炎症疾病。我们证明了募集A20所需的功能ZnF7结构域，用于肿瘤坏死因子受体1（TNFR1）信号络合物并抑制炎症信号传导和细胞死亡。 ZnF4和ZnF7的组合灭活与A20缺陷小鼠的产后致死性和严重的多功能炎症都是Hapcococeied。突变A20的条件组织特异性表达进一步揭示了泛素结合在髓样和肠上皮细胞中的关键作用。总的来说，这些结果表明A20的抗炎和细胞保护功能在很大程度上取决于其泛素结合性质。

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