Regulation of IκB kinase-related kinases and antiviral responses by tumor suppressor CYLD
Regulation of IκB kinase-related kinases and antiviral responses by tumor suppressor CYLD
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DOI：
10.1074/jbc.m801451200
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发表时间：
2008-07-04
影响因子：
4.8
通讯作者：
Sun, Shao-Cong
中科院分区：
文献类型：
--
作者：
Zhang, Minying;Wu, Xuefeng;Sun, Shao-Cong
I Kappa B激酶（IKK）相关的激酶IKK EPSILON和TBK1参与病毒感染期间I型干扰素（IFNS）的诱导。 IKK EPSILON和TBK1的失调激活也有助于异常的细胞存活和转化。但是，这些激酶的受负调节尚不清楚。我们在这里表明，肿瘤抑制剂CYLD在防止异常激活IKK EPSILON/TBK1方面具有至关重要的作用。 CYLD缺乏会导致IKK Epsilon/TBK1的组成型激活，这与病毒感染细胞中IFN的过度诱导有关。我们进一步表明，CYLD靶向细胞质RNA传感器RIG-I，并抑制该IKK EPSILON/TBK1刺激剂的泛素化。与RIG-1功能中泛素化的需求一致，CYLD有效地抑制了IFN-beta启动子的RIG-I介导的激活。这些发现将CYLD作为IKK Epsilon/TBK1的关键负调节剂建立，并提出了CYLD在控制Rig-I泛素化中的作用。
The I kappa B kinase (IKK)-related kinases, IKK epsilon and TBK1, participate in the induction of type I interferons (IFNs) during viral infections. Deregulated activation of IKK epsilon and TBK1 also contributes to the abnormal cell survival and transformation. However, how these kinases are negatively regulated remains unclear. We show here that the tumor suppressor CYLD has an essential role in preventing aberrant activation of IKK epsilon/TBK1. CYLD deficiency causes constitutive activation of IKK epsilon/TBK1, which is associated with hyper-induction of IFNs in virus-infected cells. We further show that CYLD targets a cytoplasmic RNA sensor, RIG-I, and inhibits the ubiquitination of this IKK epsilon/TBK1 stimulator. Consistent with the requirement of ubiquitination in RIG-I function, CYLD potently inhibits RIG-I-mediated activation of the IFN-beta promoter. These findings establish CYLD as a key negative regulator of IKK epsilon/TBK1 and suggest a role for CYLD in the control of RIG-I ubiquitination.