CYLD is a deubiquitinating enzyme that negatively regulates NF-κB activation by TNFR family members
CYLD is a deubiquitinating enzyme that negatively regulates NF-κB activation by TNFR family members
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DOI：
10.1038/nature01803
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发表时间：
2003-08-14
期刊：
影响因子：
64.8
通讯作者：
Mosialos, G
中科院分区：
文献类型：
--
作者：
Trompouki, E;Hatzivassiliou, E;Mosialos, G
家族性圆柱瘤病是一种常染色体显性遗传，易患称为圆柱瘤的皮肤附属器肿瘤。家族性圆柱瘤病是由编码CYLD蛋白的基因突变引起的，该蛋白的功能以前未知（1）。在这里，我们表明，CYLD是一种去泛素化酶，负调控激活转录因子NF-κ B的特异性肿瘤坏死因子受体（TNFRs）。CYLD去泛素化活性的丧失与肿瘤发生相关。CYLD以依赖于CYLD的去泛素化活性的方式抑制TNFR家族成员CD 40、XEDAR和EDAR对NF-κ B的活化。通过RNA介导的干扰下调CYLD增强了基础和CD 40介导的NF-κ B活化。CYLD对NF-κ B活化的抑制至少部分是通过TNFR相关因子2（TRAF 2）的去泛素化和失活介导的，在较小程度上，TRAF 6也是如此。这些结果表明，CYLD是一个负调节剂的尼古丁介导的激活NF-κ B，需要适当的细胞稳态的皮肤附件。
Familial cylindromatosis is an autosomal dominant predisposition to tumours of skin appendages called cylindromas. Familial cylindromatosis is caused by mutations in a gene encoding the CYLD protein of previously unknown function(1). Here we show that CYLD is a deubiquitinating enzyme that negatively regulates activation of the transcription factor NF-kappaB by specific tumour-necrosis factor receptors (TNFRs). Loss of the deubiquitinating activity of CYLD correlates with tumorigenesis. CYLD inhibits activation of NF-kappaB by the TNFR family members CD40, XEDAR and EDAR in a manner that depends on the deubiquitinating activity of CYLD. Downregulation of CYLD by RNA-mediated interference augments both basal and CD40-mediated activation of NF-kappaB. The inhibition of NF-kappaB activation by CYLD is mediated, at least in part, by the deubiquitination and inactivation of TNFR-associated factor 2 (TRAF2) and, to a lesser extent, TRAF6. These results indicate that CYLD is a negative regulator of the cytokine-mediated activation of NF-kappaB that is required for appropriate cellular homeostasis of skin appendages.