AKT1 distinctively suppresses MyD88-depenedent and TRIF-dependent Toll-like receptor signaling in a kinase activity-independent manner
AKT1 distinctively suppresses MyD88-depenedent and TRIF-dependent Toll-like receptor signaling in a kinase activity-independent manner
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DOI：
10.1016/j.cellsig.2017.12.002
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发表时间：
2018-03-01
影响因子：
4.8
通讯作者：
Tanamoto, Ken-ichi
中科院分区：
文献类型：
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作者：
Zenke, Kosuke;Muroi, Masashi;Tanamoto, Ken-ichi
我们发现，作为PI3K-AKT信号传导的主要效应分子，AKT1通过抑制NF-KB激活和IRF3活性而独立于其激酶活性，显著抑制Toll样受体（TLR）介导的myd88依赖性和Toll/IL-1R结构域适配器诱导的ifn - β (TRIF)依赖性信号传导。在AKT1敲除RAW264.7细胞中，与野生型细胞相比，脂多糖（LPS）诱导的IL-1 β和tnf - α（由myd88依赖途径调节）以及ifn - β和RANTES （C-C基序趋化因子配体5:CCL-5，由trif依赖途径调节）的转录和蛋白产生增强。在LPS刺激下，AKT1敲除细胞也表现出NF-kappa B和IFN-13启动子活性增强，通过与AKT1或其激酶死亡突变体（AKT1- kd）互补，这些启动子活性降低到与野生型细胞相当的水平。在野生型细胞中，表达AKT1或AKT1- kd类似地抑制LPS和其他TLR配体诱导的NF-KB和IFN-13启动子活性。对TLR信号通路中myd88依赖通路相关蛋白的瞬时表达引起的NF-kappa B激活的分析显示，AKT1抑制IKK β和NF-kappa B激活之间发生的信号传导。相反，AKT1似乎通过抑制IRF3活性本身来抑制ifn - β启动子。这些结果表明，AKT1具有一种新的非激酶功能，可以抑制TLR信号传导，并提示AKT1具有多种功能。
We found that AKT1, a primary effector molecule of PI3K-AKT signaling, distinctively suppressed Toll-like receptor (TLR)-mediated MyD88-dependent and Toll/IL-1R domain-containing adaptor inducing IFN-beta (TRIF)dependent signaling by inhibiting NF-KB activation and IRF3 activity independently of its kinase activity. In AKT1 knockout RAW264.7 cells, lipopolysaccharide (LPS)-induced transcription and protein production of cytokines including IL-1 beta and TNF-alpha (regulated by the MyD88-dependent pathway), as well as IFN-beta and RANTES (C-C motif chemokine ligand 5: CCL-5; regulated by the TRIF-dependent pathways) was enhanced compared to wild type cells. In response to LPS stimulation, AKT1 knockout cells also exhibited enhanced NF-kappa B and IFN-13 promoter activities, which were reduced to a level comparable to that in wild type cells by complementation with either AKT1 or its kinase-dead mutant (AKT1-KD). Expression of AKT1 or AKT1-KD similarly suppressed NF-KB and IFN-13 promoter activities induced by LPS and other TLR ligands in wild type cells. Analysis of NF-kappa B activation caused by transient expression of proteins involved in the MyD88-dependent pathway in TLR signaling revealed that AKT1 suppressed signaling that occurs between activation of IKK beta and that of NF-kappa B. In contrast, AKT1 appeared to suppress the IFN-beta promoter through inhibition of IRF3 activity itself. These results demonstrate a novel, non-kinase function of AKT1 that inhibits TLR signaling, and suggest the multifunctional nature of AKT1.