Inhibition of cGAS-Mediated Interferon Response Facilitates Transgene Expression

Fu, Yajuan; Fang, Yijun; Zhang, Lin; Yang, Linqi; Zheng, Liqun; Hu, Hao; Yu, Tingting; Huang, Baoquan; Chen, Suxing; Wang, Hanze; Xu, Shan; Wang, Bao; Chen, Qi; Sun, Lijun

doi:10.1016/j.isci.2020.101026

Cited by 26 publications

(17 citation statements)

References 44 publications

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“…We then examined the mRNA expression level of a number of known downstream target genes of the cGAS-STING pathway. Consistent with the previous studies ( Sun et al, 2013 ; Parkes et al, 2017 ; Fu et al, 2020 ), Talazoparib treatment greatly upregulated the expression of type I interferons (IFN; Inf-α and Inf-β ), pro-inflammatory cytokines ( Ccl5 and Cxcl10 ), and interferon-stimulated genes (ISGs; Isg15 , Mx1 , Mx2 , and Ifit3 ) ( Figure 1F , Figure 1—figure supplement 1A ). To examine whether the cGAS-STING pathway is necessary for the PARPi-induced innate immune signaling, we depleted cGAS using two independent short hairpin RNAs (shRNAs) ( Figure 1G ).…”

Section: Resultssupporting

confidence: 90%

PARP1 inhibitors trigger innate immunity via PARP1 trapping-induced DNA damage response

Kim

Wang

2020

eLife

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It is being increasingly appreciated that the immunomodulatory functions of PARP inhibitors (PARPi) underlie their clinical activities in various BRCA-mutated tumors. PARPi possess both PARP1 inhibition and PARP1 trapping activities. The relative contribution of these two mechanisms toward PARPi-induced innate immune signaling, however, is poorly understood. We find that the presence of the PARP1 protein with uncompromised DNA-binding activities is required for PARPi-induced innate immune response. The activation of cGAS-STING signaling induced by various PARPi closely depends on their PARP1 trapping activities. Finally, we show that a small molecule PARP1 degrader blocks the enzymatic activity of PARP1 without eliciting PARP1 trapping or cGAS-STING activation. Our findings thus identify PARP1 trapping as a major contributor of the immunomodulatory functions of PARPi. Although PARPi-induced innate immunity is highly desirable in human malignancies, the ability of “non-trapping” PARP1 degraders to avoid the activation of innate immune response could be useful in non-oncological diseases.

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Section: Resultssupporting

confidence: 90%

PARP1 inhibitors trigger innate immunity via PARP1 trapping-induced DNA damage response

Kim

Wang

2020

eLife

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“…37 In regards to nonviral gene delivery, the inhibition of STING with small molecule inhibitors (C176, C178) has been shown to enhance transgene expression by up to 3-fold in a variety of cell lines, including primary T cells. 38 These previous studies and our observations collectively emphasize the importance of the STING DNA sensing pathway and suggest that targeting STING for inhibition may be an effective strategy to improve the potency of gene therapy treatments.…”

Section: Differences In Dna Sensing Pathwayssupporting

confidence: 71%

Transcriptomic Analysis of the Innate Immune Response toin vitroTransfection of Plasmid DNA

Warga

Tucker

Harris

et al. 2021

Preprint

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The innate immune response to cytosolic DNA is intended to protect the host from viral infections, but it can also inhibit the delivery and expression of therapeutic transgenes in gene and cell therapies. The goal of this work was to use mRNA-sequencing to reveal correlations between the transfection efficiencies of four cell types (PC-3, Jurkat, HEK-293T, and primary CD3+ T cells) and their innate immune responses to nonviral gene delivery. Overall, the highest transfection efficiency was observed in HEK-293T cells (87%), which upregulated only 142 genes with no known anti-viral functions. Lipofection upregulated a much larger number (n = 1,057) of cytokine-stimulated genes (CSGs) in PC-3 cells, which also exhibited a significantly lower transfection efficiency. However, the addition of serum during Lipofection and electroporation significantly increased transfection efficiencies and decreased the number of upregulated genes in PC-3 cells. Finally, while Lipofection of Jurkat and Primary T cells only upregulated a few genes, several anti-viral CSGs that were absent in HEK and upregulated in PC-3 cells were observed to be constitutively expressed in T cells, which may explain their relatively low Lipofection efficiencies (8-21%). Indeed, overexpression of one such CSG (IFI16) significantly decreased transfection efficiency in HEK cells to 33%.

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“…In addition, our research group found that inhibition of cGAS by gene knockout or chemical inhibition can increase transgene expression at the transcriptional level, and that this increase is negatively correlated with IFN and interferon-stimulated gene (ISG) expression (78). Thus, targeting the cGAS-STING signaling pathway is likely an effective strategy for gene therapy and nucleic acid drug development.…”

Section: A Variety Of Nucleic Acid Species Are Sensed By Cgas Cgas Re...mentioning

confidence: 99%

A Variety of Nucleic Acid Species Are Sensed by cGAS, Implications for Its Diverse Functions

et al. 2022

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Cyclic GMP-AMP synthase (cGAS) recognizes double-stranded DNA (dsDNA) derived from invading pathogens and induces an interferon response via activation of the key downstream adaptor protein stimulator of interferon genes (STING). This is the most classic biological function of the cGAS-STING signaling pathway and is critical for preventing pathogenic microorganism invasion. In addition, cGAS can interact with various types of nucleic acids, including cDNA, DNA : RNA hybrids, and circular RNA, to contribute to a diverse set of biological functions. An increasing number of studies have revealed an important relationship between the cGAS-STING signaling pathway and autophagy, cellular senescence, antitumor immunity, inflammation, and autoimmune diseases. This review details the mechanism of action of cGAS as it interacts with different types of nucleic acids, its rich biological functions, and the potential for targeting this pathway to treat various diseases.

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Inhibition of cGAS-Mediated Interferon Response Facilitates Transgene Expression

Cited by 26 publications

References 44 publications

PARP1 inhibitors trigger innate immunity via PARP1 trapping-induced DNA damage response

PARP1 inhibitors trigger innate immunity via PARP1 trapping-induced DNA damage response

Transcriptomic Analysis of the Innate Immune Response toin vitroTransfection of Plasmid DNA

A Variety of Nucleic Acid Species Are Sensed by cGAS, Implications for Its Diverse Functions

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