Simian virus 40 large T antigen induces IFN-stimulated genes through ATR kinase.
Simian virus 40 large T antigen induces IFN-stimulated genes through ATR kinase.
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DOI：
10.4049/jimmunol.1303470
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发表时间：
2014-06-15
期刊：
影响因子：
--
通讯作者：
Sarkar SN
中科院分区：
文献类型：
--
作者：
Forero A;Giacobbi NS;McCormick KD;Gjoerup OV;Bakkenist CJ;Pipas JM;Sarkar SN
Polyomaviruses encode a Large T antigen (LT), a multifunctional protein essential for the regulation of both viral and host cell gene expression and productive viral infection. Previously, we have shown that stable expression of LT protein results in upregulation of genes involved in the interferon induction and signaling pathway. In this study, we focus on the cellular signaling mechanism that leads to the induction of interferon (IFN) responses by LT. Our results show that ectopic expression of Simian virus 40 (SV40) LT results in the induction of interferon-stimulated genes (ISGs) in human fibroblasts and confers an antiviral state. We describe a LT-initiated DNA-damage response (DDR) that activates IRF1 causing IFNβ production and consequent ISG expression in human cells. This IFNβ and ISG induction is dependent on ATM and Rad3 related (ATR) kinase, but independent of ataxia-telangiectasia mutated (ATM). ATR kinase inhibition using a selective kinase inhibitor (ETP-46464) caused a decrease in IRF1 stabilization and ISG expression. Furthermore, expression of a mutant LT that does not induce DDR, does not induce IFNβ and ISGs. These results show that in the absence of viral infection, LT-initiated activation of ATR-dependent DDR is sufficient for the induction of an IFNβ-mediated innate immune response in human cells. Thus, we have uncovered a novel and critical role for ATR as a mediator of antiviral responses utilizing LT.
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DOI：
10.1126/science.1240925
发表时间：
2013-08-16
期刊：
Science (New York, N.Y.)
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