Detection of viral DNA and production of type I interferons (IFNs) are essential for antiviral immunity and immune responses against transformed cells; on the other hand, inappropriate immune responses to self DNA result in autoimmunity. Intracellular DNA sensing activates the STING-dependent IFN stimulatory DNA (ISD) pathway. Multiple DNA sensors have been proposed to activate the ISD pathway, including cyclic GMP-AMP synthase (cGAS) and a family of DNA binding receptors called the AIM2-like receptors (ALRs). Analysis of cGAS-deficient mice has revealed that cGAS is required for the IFN response to transfected DNA ligands, DNA viruses, and retroviruses. In contrast, while multiple studies have suggested that ALRs promote an optimal IFN response to various DNA pathogens, others have found that the IFN response is intact following ALR knockdown. Thus, while cGAS has clearly emerged as a key DNA sensor in the ISD pathway, the function of the ALRs remains unclear.
To define the relative contributions of the ALRs and cGAS to the ISD pathway, we generated mice lacking all thirteen ALR genes and cGAS-deficient mice. In addition, we have used CRISPR gene targeting to disrupt cGAS and all four human ALRs in human cells. Analysis of IFN induction following transfection of DNA ligands or DNA virus infection has revealed that cGAS is absolutely required for activation of the ISD pathway in both mouse and human cells, consistent with recent studies. In contrast, the IFN response to transfected DNA ligands and infection with a variety of DNA viruses is intact in ALR-deficient cells, suggesting that the ALRs may be dispensable for activation of the ISD pathway. We are currently exploring potential alternative functions of the ALR family of DNA binding receptors.
Citation Format: Elizabeth Gray, Daniel Stetson. Functional analysis of DNA sensors in the interferon stimulatory DNA (ISD) pathway. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A167.
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