Receptor-interacting protein homotypic interaction motif-dependent control of NF-kappa B activation via the DNA-dependent activator of IFN regulatory factors.
Receptor-interacting protein homotypic interaction motif-dependent control of NF-kappa B activation via the DNA-dependent activator of IFN regulatory factors.
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DOI：
10.4049/jimmunol.181.9.6427
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发表时间：
2008-11-01
期刊：
影响因子：
--
通讯作者：
Mocarski ES
中科院分区：
文献类型：
--
作者：
Kaiser WJ;Upton JW;Mocarski ES
DNA依赖性IFN调节因子激活因子（IRF； DAI，也称为ZBP1或DLM-1）是胞质DNA传感器，启动IRF3和NF-κB通路，导致I型IFN （IFNα, IFNβ）和其他细胞因子的激活。在这项研究中，NF-κB的诱导被证明依赖于适配器受体相互作用蛋白激酶（RIP）1，通过RIP同型相互作用基序（RHIM）依赖于DAI的相互作用。DAI与内源性RIP1在细胞质颗粒上结合并共定位。RNAi抑制RIP1表达可抑制NF-κB活化和免疫刺激DNA诱导的IFNβ。DAI还与RIP3相互作用，这种相互作用增强了DAI介导的NF-κB活化，暗示RIP3调节了这种依赖于rhm的途径。DAI在响应免疫刺激DNA激活NF-κB中的作用似乎类似于TLR3对dsRNA的感知，因为这两种途径都涉及通过RIP1介导的rhm依赖信号，强化了该适配器在细胞内微生物先天感知中的核心作用。
DNA-dependent activator of IFN regulatory factors (IRF; DAI, also known as ZBP1 or DLM-1) is a cytosolic DNA sensor that initiates IRF3 and NF-κB pathways leading to activation of type I IFNs (IFNα, IFNβ) and other cytokines. In this study, induction of NF-κB is shown to depend on the adaptor receptor-interacting protein kinase (RIP)1, acting via a RIP homotypic interaction motif (RHIM)-dependent interaction with DAI. DAI binds to and colocalizes with endogenous RIP1 at characteristic cytoplasmic granules. Suppression of RIP1 expression by RNAi abrogates NF-κB activation as well as IFNβ induction by immunostimulatory DNA. DAI also interacts with RIP3 and this interaction potentiates DAI-mediated activation of NF-κB, implicating RIP3 in regulating this RHIM-dependent pathway. The role of DAI in activation of NF-κB in response to immunostimulatory DNA appears to be analogous to sensing of dsRNA by TLR3 in that both pathways involve RHIM-dependent signaling that is mediated via RIP1, reinforcing a central role for this adaptor in innate sensing of intracellular microbes.
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