A20 restricts ubiquitination of pro-interleukin-1β protein complexes and suppresses NLRP3 inflammasome activity.
A20 restricts ubiquitination of pro-interleukin-1β protein complexes and suppresses NLRP3 inflammasome activity.
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DOI：
10.1016/j.immuni.2014.12.031
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发表时间：
2015-01-20
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：
Duong, Bao H.;Onizawa, Michio;Oses-Prieto, Juan A.;Advincula, Rommel;Burlingame, Alma;Malynn, Barbara A.;Ma, Averil
不适当的炎性小体激活有助于多种人类疾病，但抑制炎性小体的机制知之甚少。NFκB抑制剂A20是一种泛素修饰酶，可预防人类炎症性疾病和淋巴瘤。在这里，我们报告说，A20缺陷型巨噬细胞，不像正常细胞，表现出自发的NLRP 3炎性体活性，单独的LPS。这种反应需要激酶RIPK 3，而不是衔接子MyD 88。在正常细胞中，A20与半胱天冬酶-1和pro-IL-1β组成性结合，NLRP 3活化进一步促进A20募集至炎性小体。Pro-IL-1β还与RIPK 1、RIPK 3、半胱天冬酶-1和半胱天冬酶-8在复合物中免疫共沉淀，该复合物被K63连接的和未锚定的聚泛素修饰。在A20缺陷型巨噬细胞中，这种pro-IL-1β相关的泛素化以RIPK 3依赖性方式显著增加。质谱和突变分析表明，IL-1β前体的K133是一个支持加工的生理性泛素化位点。我们的研究揭示了A20预防炎症性疾病的新机制。
Inappropriate inflammasome activation contributes to multiple human diseases, but the mechanisms by which inflammasomes are suppressed are poorly understood. The NFκB inhibitor A20 is a ubiquitin-modifying enzyme that may prevent human inflammatory diseases and lymphomas. Here, we report that A20-deficient macrophages, unlike normal cells, exhibit spontaneous NLRP3 inflammasome activity to LPS alone. The kinase RIPK3, but not the adaptor MyD88, is required for this response. In normal cells, A20 constitutively associates with caspase-1 and pro-IL-1β, and NLRP3 activation further promotes A20 recruitment to the inflammasome. Pro-IL-1β also co-immunoprecipitates with RIPK1, RIPK3, caspase-1 and caspase-8 in a complex that is modified with K63-linked and unanchored polyubiquitin. In A20-deficient macrophages, this pro-IL-1β-associated ubiquitination is markedly increased in a RIPK3-dependent manner. Mass spectrometric and mutational analyses reveal that K133 of pro-IL-1β is a physiological ubiquitination site that supports processing. Our study reveals a novel mechanism by which A20 prevents inflammatory diseases.
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