Poster abstracts
Poster number 42 submitted by Trupti Devale
Role of stress granules in dsDNA activated Stimulator of Interferon Genes (STING) signaling pathway
Trupti Devale (Department of Biological Sciences, University of Toledo), Praveen Manivannan (Department of Microbiology and Immunology, University of Michigan), Malathi Krishnamurthy (Department of Biological Sciences, University of Toledo)
Abstract:
Presence of cytosolic double stranded (ds)DNA triggers a danger signal and can activate multiple DNA sensors including cyclic GMP-AMP synthase (cGAS) resulting in cascade of immune signaling pathways for host defense. These receptors can activate Stimulator of Interferon Genes (STING), a key Endoplasmic Reticulum (ER) resident protein critical to mounting immune response against dsDNA. Activated STING signals through TBK1/IRF3/IFN axis to clear cytosolic dsDNA. Our preliminary studies demonstrate that overexpression of STING or treatment with dsDNA analog, pdA:dT, is able to activate the STING pathway, IFN-β induction and also induce stress granules (SG). In response to dsDNA, we show that ER resident kinase PERK is involved in phosphorylating translation initiation factor eIF2α, which is required for SG formation and inhibiting PERK significantly reduces this effect. Our results suggest the requirement of PERK and SG assembly in coordinating signals to enhance IFN-β production in response to dsDNA. We also show that in absence of STING, induction of IFN-β, ISG 56 and proinflammatory cytokines is significantly reduced in response to dsDNA. Based on previous literature studies and our preliminary data, we show that dsDNA can signal through RNA binding ligand RIG-I to induce IFN-β production, which is significantly abrogated in absence of RIG-I. We also explore the possibility of crosstalk between these key proteins in our interaction studies which show dsDNA promotes STING and RIG-I interaction. Although these signaling pathways can induce IFN-β independently, we propose that these pathways work synergistically to augment IFN-β production in response to DNA viruses. Further studies will address identifying dsDNA receptor activating STING signaling, composition and localization of key proteins in SG formed in response to dsDNA, role of SG in crosstalk between STING and RIG-I signaling. These studies will help identify minimal molecular features of immunostimulatory DNA that can be used as adjuvant for antiviral therapies.
Keywords: stress granaules G3BP1, cGAS STING, innate immune signaling