A20 is a negative regulator of IFN regulatory factor 3 signaling
A20 is a negative regulator of IFN regulatory factor 3 signaling
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DOI：
10.4049/jimmunol.174.3.1507
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发表时间：
2005-02-01
影响因子：
4.4
通讯作者：
Yamaoka, S
中科院分区：
文献类型：
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作者：
Saitoh, T;Yamamoto, M;Yamaoka, S
IFN调节因子3 （IR-F-3）是一种关键的转录因子，在检测到病毒病原体后调节先天免疫状态的建立。最近的研究揭示了两种IKK样激酶。nt - kappab激活激酶/Traf家族成员相关的NF-kappaB激活剂结合激酶1和IKK-i/IKKepsilon。负责IRF-3的激活。但IRF-3信号通路的调控机制尚不完全清楚。在这项研究中，我们报道了IRF-3的激活被A20抑制，A20最初被鉴定为细胞凋亡抑制剂，并被dsRNA诱导表达。A-30与NF-kappaB激活激酶/Traf家族成员相关的NF-kappaB激活因子结合激酶I和IKK-iKKepsilon物理相互作用。并在dsRNA或新城疫病病毒感染TLR3后抑制IRF-3的二聚化，导致IFN刺激反应元件和IFN- β启动子依赖性转录的抑制。重要的是，通过RNA干扰敲低A20的表达会导致刺激TLR3或病毒感染引发的irf -3依赖性转录增强。因此，我们的研究表明，A20是先天抗病毒反应中IRF-3激活信号级联的候选负调节因子。
IFN regulatory factor 3 (IR-F-3) is a critical transcription factor that regulates an establishment of innate immune status following detection of viral pathogens. Recent studies have revealed that two IkappaB kinase (IKK)-like kinases. NT-kappaB-activating kinase/Traf family member-associated NF-kappaB activator-binding kinase 1 and IKK-i/IKKepsilon. are responsible for activation of IRF-3. but the regulatory mechanism of the IRF-3 signaling pathway has not been fully understood. In this study, we report that IRF-3 activation is suppressed by A20, which was initially identified as an inhibitor of apoptosis and inducibly expressed by dsRNA. A-30 physically interacts with NF-kappaB -activating kinase/Traf family member-associated NF-kappaB activator-binding kinase I and IKK-iKKepsilon. and inhibits dimerization of IRF-3 following engagement of TLR3 by dsRNA or Newcastle disease virus infection, leading to suppression of the IFN stimulation response element- and IFN-beta promoter-dependent transcription. Importantly, knocking down of A20 expression by RNA interference results in enhanced IRF-3-dependent transcription triggered by the stimulation of TLR3 or virus infection. Our study thus demonstrates that A20 is a candidate negative regulator of the signaling cascade to IRF-3 activation in the innate antiviral response.