Regulation of the cGAS-STING Pathway in Health and Disease




Pokatayev, Vladislav Andreyevich

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The innate immune system senses non-self or altered-self molecular structures through pattern recognition receptors in order to eliminate pathogens or damaged cells, and restore an organism to its basal physiology. Nearly all nucleated cell types can sense intracellular viral nucleic acids. These sensors detect either viral RNA through RIG-I like receptors or DNA through the cGAS-STING signaling pathway. Antiviral immune pathways are vital for resolution of viral infections; however, their dysregulation may give rise to various immune-mediated diseases. The neuro-inflammatory autoimmune disease Aicardi-Goutières Syndrome (AGS) develops from mutations in genes encoding several nucleic acid processing proteins, including RNase H2. Defective RNase H2 may induce accumulation of self-nucleic acid species which trigger chronic inflammation leading to AGS pathology. We created a knock-in mouse model with an RNase H2 AGS mutation in a highly conserved residue of the catalytic subunit, Rnaseh2aG37S/G37S (G37S), the most severe Rnaseh2a mutation categorized as it abolishes nuclease activity to less than 10% of WT RNase H2, to understand disease pathology. Importantly, I found that the G37S mutation induces a cellular anti-viral state, and an increased expression of interferon-stimulated genes dependent on the cGAS-STING signaling pathway. G37S homozygotes are perinatal lethal, and ablation of STING in G37S mice results in partial rescue of the perinatal lethality and complete rescue of the immune phenotype. This study motivates inhibitors of the cGAS-STING pathway in the goal of resolving Rnaseh2a-mediated AGS. As my previous work implicates STING in the development of AGS, I performed a genetic screen to identify novel regulators of this protein. I discovered that TOLLIP, a protein previously identified as a regulator of extracellular Toll-like receptor pathways, can function as a positive regulator of the cGAS-STING pathway. TOLLIP antagonizes STING protein degradation through a regulatory pathway controlled by the protein IRE1α. In Tollip-/- cells, IRE1α is activated and induces lysomal-mediated degradation of STING. Chronic activation of this degradative pathway blunts the cellular response to cGAS or STING agonists. These findings have implications in vivo, as deleting Tollip in a mouse model for AGS, the Trex1-/- mouse, can rescue symptoms of the disease. These findings have clinical importance, as novel therapeutics against TOLLIP can be developed to treat auto-inflammation caused by dysregulation of the cGAS-STING signaling pathway.

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Pages v-xiii are misnumbered as pages vi-xiv.

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