Deubiquitination of NLRP3 by BRCC3 Critically Regulates Inflammasome Activity
Deubiquitination of NLRP3 by BRCC3 Critically Regulates Inflammasome Activity
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DOI：
10.1016/j.molcel.2012.11.009
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发表时间：
2013-01-24
期刊：
影响因子：
16
通讯作者：
Yuan, Junying
中科院分区：
文献类型：
--
作者：
Py, Benedicte F.;Kim, Mi-Sung;Yuan, Junying
NLRP 3是一种重要的模式识别受体，参与介导炎症小体活化，以响应病毒和细菌感染以及与组织损伤或功能障碍相关的各种促炎刺激。在活化后，NLRP 3组装包含衔接子ASC和效应物半胱天冬酶原-1的多聚体炎性体复合物以介导半胱天冬酶-1的活化。虽然NLRP 3的表达是由NF-κ B B途径诱导的，但控制NLRP 3活化的转录后分子机制仍然不清楚。使用药理学和分子方法，我们表明，NLRP 3炎性体的激活是由去泛素化机制调节的。我们进一步确定的去泛素化酶，BRCC 3，作为一个关键的调节NLRP 3活性，促进其去泛素化和表征NLRP 3作为底物的细胞溶质BRCC 3的BRISC复合物。我们的研究结果阐明了涉及BRCC 3依赖性NLRP 3调节的调节机制，并强调NLRP 3泛素化是炎症性疾病的潜在治疗靶点。
NLRP3 is an important pattern recognition receptor involved in mediating inflammasome activation in response to viral and bacterial infections as well as various proinflammatory stimuli associated with tissue damage or malfunction. Upon activation, NLRP3 assembles a multimeric inflammasome complex comprising the adaptor ASC and the effector pro-caspase-1 to mediate the activation of caspase-1. Although NLRP3 expression is induced by the NF-kappa B pathway, the posttranscriptional molecular mechanism controlling the activation of NLRP3 remains elusive. Using both pharmacological and molecular approaches, we show that the activation of NLRP3 inflammasome is regulated by a deubiquitination mechanism. We further identify the deubiquitinating enzyme, BRCC3, as a critical regulator of NLRP3 activity by promoting its deubiquitination and characterizing NLRP3 as a substrate for the cytosolic BRCC3-containing BRISC complex. Our results elucidate a regulatory mechanism involving BRCC3-dependent NLRP3 regulation and highlight NLRP3 ubiquitination as a potential therapeutic target for inflammatory diseases.