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Inhibition of cGAS-Mediated Interferon Response Facilitates Transgene Expression.
iScience ( IF 5.8 ) Pub Date : 2020-03-31 , DOI: 10.1016/j.isci.2020.101026
Yajuan Fu 1 , Yijun Fang 1 , Zhang Lin 1 , Lei Yang 1 , Liqun Zheng 1 , Hao Hu 1 , Tingting Yu 1 , Baoting Huang 1 , Suxing Chen 1 , Hanze Wang 1 , Shan Xu 1 , Wei Bao 2 , Qi Chen 1 , Lijun Sun 1
Affiliation  

DNA transfection is often the bottleneck of research and gene therapy practices. To explore the mechanism regulating transgene expression, we investigated the role of the cGAS-STING signaling pathway, which induces type-I interferons in response to DNA. We confirmed that deletion of cGAS enhances transgene expression at the protein level by ~2- to 3-fold. This enhancement is inversely correlated with the expression of interferons and interferon stimulated genes (ISGs), which suppress expression of transfected genes at the mRNA level. Mechanistically, DNA transfection activates the cGAS-STING pathway and induces the expression of the OAS family proteins, leading to the activation of RNaseL and degradation of mRNA derived from transgenes. Administration of chemical inhibitors that block cGAS-mediated signaling cascades improves the expression of transgenes by ~1.5- to 3-fold in multiple cell lines and primary cells, including T cells. These data suggest that targeting the cGAS-STING pathway can improve transgene expression, and this strategy may be applied to gene therapy.



中文翻译:

cGAS介导的干扰素反应的抑制促进转基因表达。

DNA转染通常是研究和基因治疗实践的瓶颈。为探讨调节转基因表达的机制,我们研究了cGAS-STING信号传导途径的作用,该途径可诱导对DNA的I型干扰素。我们证实删除cGAS可以在蛋白质水平上将转基因表达提高2到3倍。这种增强与干扰素和干扰素刺激基因(ISG)的表达呈反相关,后者在mRNA水平上抑制了转染基因的表达。从机制上讲,DNA转染激活cGAS-STING途径并诱导OAS家族蛋白的表达,从而导致RNaseL的激活和源自转基因的mRNA的降解。在多种细胞系和原代细胞(包括T细胞)中,阻断cGAS介导的信号级联反应的化学抑制剂的给药可使转基因的表达提高约1.5至3倍。这些数据表明靶向cGAS-STING途径可以改善转基因表达,并且该策略可以应用于基因治疗。

更新日期:2020-03-31
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