Project description:Loss of SAMHD1 causes chronic activaiton of the MDA5/MAVS dsRNA sensing pathway, only when cGAS/STING signaling is intact. Peritoneal macrophages from mutant and control mice were isolated by FACS. Total RNA was subjected to next generation mRNA sequencing.
Project description:Loss of SAMHD1 causes chronic activaiton of the MDA5/MAVS dsRNA sensing pathway, only when cGAS/STING signaling is intact. Peritoneal macrophages from mutant and control mice were isolated by FACS. Total RNA was subjected to next generation mRNA sequencing.
Project description:SAMHD1 is a restriction factor for HIV-1 infection. SAMHD1 mutations cause the autoinflammatory Aicardi-Goutières syndrome that is characterized by chronic type I interferon (IFN) secretion. We show that the spontaneous IFN response in SAMHD1-deficient cells and mice requires the cGAS/STING cytosolic DNA-sensing pathway. We provide genetic evidence that cell-autonomous control of lentivirus infection in myeloid cells by SAMHD1 limits virus-induced production of IFNs and the induction of co-stimulatory markers. This program of myeloid cell activation required reverse transcription, cGAS and STING, and signaling through the IFN receptor. Furthermore, SAMHD1 reduced the induction of virus-specific cytotoxic T cells in vivo. Therefore, virus restriction by SAMHD1 limits the magnitude of IFN and T cell responses. This demonstrates a competition between cell-autonomous virus control and subsequent innate and adaptive immune responses, a concept with important implications for the treatment of infection.
Project description:Tumors with defective mismatch repair (dMMR) are responsive to immunotherapy because of dMMR-induced neoantigens and activation of the cGAS-STING pathway. While neoantigens result from the hypermutable nature of dMMR, it is unknown how dMMR activates the cGAS-STING pathway. We show here that loss of the MutLα subunit MLH1, whose defect is responsible for ~50% of dMMR cancers, results in loss of MutLα-specific regulation of exonuclease 1 (Exo1) during DNA repair. This leads to unrestrained DNA excision by Exo1, which causes increased single-strand DNA formation, RPA exhaustion, DNA breaks, and aberrant DNA repair intermediates. Ultimately, this generates chromosomal abnormalities and the release of nuclear DNA into the cytoplasm, activating the cGAS-STING pathway. In this study, we discovered a hitherto unknown MMR mechanism that modulates genome stability and has implications for cancer therapy.
Project description:We show that Manganese (II) is a potent type I-IFN inducing agonist, stimulating cells into an anti-viral state in the absence of infection. Mechanically, Mn2+ treatment led to a profound cGAS-STING-dependent innate immune activation, conferring cells or mice viral resistance.
