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A genome-wide map of the genetic network in monocytes that regulates type I interferon induction by the cGAS-STING pathway

ABSTRACT: Type I interferons (IFNs) are induced by pattern recognition receptors (PRRs) of the innate immune system to protect against foreign pathogens and malignant transformation, and their production must be tightly regulated to balance antiviral defense with tissue homeostasis. To define the genetic network that governs IFN regulation, we conducted genome-wide CRISPR screens for genes that positively or negatively regulated IFNB1 gene expression induced by the PRR cGAS and its downstream effector STING, in both unprimed THP-1 cells and cells primed with IFN-α to mimic an ongoing inflammatory response. Distinct subsets of genes affected IFNB1 induction in the unprimed and primed states, and many regulators had not previously been associated with IFN responses, thereby linking IFNB1 regulation to various cellular pathways. For example, we found that the NCoR/SMRT corepressor complex components TBL1XR1 and HDAC3 cooperated to support IFNB1 expression, with HDAC3 promoting activation of the kinase TBK1, an essential driver of type I IFN responses. These datasets are a resource for identifying genes associated with type I IFN-related inborn errors of immunity and cancer and for developing therapies to modulate STING signaling in interferonopathies and other conditions of dysregulated type I IFN.

ORGANISM(S): synthetic construct

PROVIDER: GSE288238 | GEO | 2026/08/18

REPOSITORIES: GEO

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Project description:Type I interferon (IFN) response is the most recognized signaling activity of STING, and IFN signaling is commonly believed to be the major (if not the sole) contributor to STING-mediated anti-viral and anti-cancer responses. Here, we genetically mutated mouse Sting serine 365 residue that is critically required for initiating IFN signaling. Sting-S365A mutation in mice precisely ablated IFN-dependent while preserving IFN-independent activities of STING. To our surprise, StingS365A/S365A mice protected against HSV-1 infection remarkably well, similar to wild type mice, while Sting–/– mice succumbed to infection very quickly. This challenges the current prevailing view and suggests that STING controls HSV-1 infection through IFN-independent activities. Transcriptomic analysis of wild type, Sting–/– and StingS365A/S365A macrophages and T cells stimulated with Sting agonist DMXAA revealed widespread IFN-independent activities of STING in both cell types and identified many T cell effector functions that are activated by STING independently of IFN. In mouse tumor models, we found that T cells in the tumor experience substantial cell death that was in part mediated by STING. Adoptively transferred Sting–/– T cells were more resistant to cell death in the tumor leading to more effective tumor control compared to wild type and StingS365A/S365A T cells. Together, our data demonstrate that mammalian STING possesses widespread IFN-independent activities that are functionally important for restricting Type I interferon (IFN) response is the most recognized signaling activity of STING, and IFN signaling is commonly believed to be the major (if not the sole) contributor to STING-mediated anti-viral and anti-cancer responses. Here, we genetically mutated mouse Sting serine 365 residue that is critically required for initiating IFN signaling. Sting-S365A mutation in mice precisely ablated IFN-dependent while preserving IFN-independent activities of STING. To our surprise, StingS365A/S365A mice protected against HSV-1 infection remarkably well, similar to wild type mice, while Sting–/– mice succumbed to infection very quickly. This challenges the current prevailing view and suggests that STING controls HSV-1 infection through IFN-independent activities. Transcriptomic analysis of wild type, Sting–/– and StingS365A/S365A macrophages and T cells stimulated with Sting agonist DMXAA revealed widespread IFN-independent activities of STING in both cell types and identified many T cell effector functions that are activated by STING independently of IFN. In mouse tumor models, we found that T cells in the tumor experience substantial cell death that was in part mediated by STING. Adoptively transferred Sting–/– T cells were more resistant to cell death in the tumor leading to more effective tumor control compared to wild type and StingS365A/S365A T cells. Together, our data demonstrate that mammalian STING possesses widespread IFN-independent activities that are functionally important for restricting HSV-1 infection, tumor immune evasion and likely also adaptive T cell immunity.

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A genome-wide map of the genetic network in monocytes that regulates type I interferon induction by the cGAS-STING pathway

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