PLX172944

GSE149744: Widespread IFN-independent activities of mammalian STING in viral infection and tumor immune evasion

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

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. SOURCE: Nan Yan (Nan.Yan@UTSouthwestern.edu) - UT Southwestern Medical Center