Akt Kinase-Mediated Checkpoint of cGAS DNA Sensing Pathway.
Akt Kinase-Mediated Checkpoint of cGAS DNA Sensing Pathway.
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DOI：
10.1016/j.celrep.2015.09.007
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发表时间：
2015-10-13
期刊：
影响因子：
8.8
通讯作者：
Jung JU
中科院分区：
文献类型：
--
作者：
Seo GJ;Yang A;Tan B;Kim S;Liang Q;Choi Y;Yuan W;Feng P;Park HS;Jung JU
在DNA刺激后，环GMP-AMP合成酶（cGAS）合成结合STING的第二信使环GMP-AMP（cGAMP），从而触发抗病毒干扰素-β（IFN-β）产生。然而，在DNA免疫原分解后，宿主如何调节cGAS酶活性仍不确定。在这里，我们表明Akt激酶在cGAS介导的抗病毒免疫应答中起着负作用。Akt分别磷酸化小鼠或人cGAS的酶结构域的S291或S305残基，并且这种磷酸化强烈抑制其酶活性。因此，活化Akt的表达导致cGAMP和IFN-β产生的减少以及单纯疱疹病毒1型复制的增加，而用Akt抑制剂处理增加cGAS介导的IFN-β产生。此外，磷酸化抗性cGAS S291 A突变体的表达增强了DNA刺激、HSV-1感染和牛痘病毒感染后的IFN-β产生。我们的研究确定了Akt激酶介导的检查点，以微调宿主对DNA刺激的免疫反应。
Upon DNA stimulation, cyclic GMP-AMP synthetase (cGAS) synthesizes the second messenger cyclic GMP-AMP (cGAMP) that binds to the STING, triggering antiviral interferon-β (IFN-β) production. However, it has remained undetermined how hosts regulate cGAS enzymatic activity after the resolution of DNA immunogen. Here, we show that Akt kinase plays a negative role in cGAS-mediated anti-viral immune response. Akt phosphorylated the S291 or S305 residue of the enzymatic domain of mouse or human cGAS, respectively, and this phosphorylation robustly suppressed its enzymatic activity. Consequently, expression of activated Akt led to the reduction of cGAMP and IFN-β production and the increase of herpes simplex virus 1 replication, whereas treatment with Akt inhibitor augmented cGAS-mediated IFN-β production. Furthermore, expression of the phosphorylation-resistant cGAS S291A mutant enhanced IFN-β production upon DNA stimulation, HSV-1 infection, and vaccinia virus infection. Our study identifies an Akt kinase-mediated checkpoint to fine-tune hosts’ immune responses to DNA stimulation.