Signalling strength determines proapoptotic functions of STING

• Published in: Nature communications Vol. 8; no. 1; pp. 427 - 10
• Main Authors: Gulen, Muhammet F., Koch, Ute, Haag, Simone M., Schuler, Fabian, Apetoh, Lionel, Villunger, Andreas, Radtke, Freddy, Ablasser, Andrea
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.09.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/1932; 631/250/1933; 631/250/262; 631/250/516; Animals; Apoptosis; Bioassays; Cytokines; Deoxyribonucleic acid; DNA; Gene expression; Human health and pathology; Humanities and Social Sciences; Immune system; Inflammation; Interferon Regulatory Factor-3 - metabolism; Intracellular signalling; Kinases; Leukemia; Leukemia, T-Cell - immunology; Leukemia, T-Cell - pathology; Life Sciences; Lymphocytes; Lymphocytes T; Medical research; Membrane Proteins - metabolism; Mice, Inbred C57BL; multidisciplinary; Pathogens; Phosphorylation; Protein Binding; Science; Science (multidisciplinary); Sensors; Signal Transduction; T-Lymphocytes - metabolism; Transcription factors; Transcription, Genetic; Tumor Suppressor Protein p53 - metabolism; Infection; Cyclic Gmp-Amp; Di-Gmp; Cgas; Innate Immune Sensor; Activation; Cytosolic Dna; 2nd-Messenger; Cells; Apoptosis
• DOI: 10.1038/s41467-017-00573-w
• ISSN: 2041-1723

Mammalian cells use cytosolic nucleic acid receptors to detect pathogens and other stress signals. In innate immune cells the presence of cytosolic DNA is sensed by the cGAS–STING signalling pathway, which initiates a gene expression programme linked to cellular activation and cytokine production. Whether the outcome of the STING response varies between distinct cell types remains largely unknown. Here we show that T cells exhibit an intensified STING response, which leads to the expression of a distinct set of genes and results in the induction of apoptosis. Of note, this proapoptotic STING response is still functional in cancerous T cells and delivery of small molecule STING agonists prevents in vivo growth of T-cell-derived tumours independent of its adjuvant activity. Our results demonstrate how the magnitude of STING signalling can shape distinct effector responses, which may permit for cell type-adjusted behaviours towards endogenous or exogenous insults. The cGAS/STING signalling pathway is responsible for sensing intracellular DNA and activating downstream inflammatory genes. Here the authors show mouse primary T cells and T leukaemia are hyperresponsive to STING agonist, and this strong STING signalling is associated with apoptosis induction.