The Mechanism of cGAS-STING Signaling in Antiviral Immunity

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2021-05-01T05:00:00.000Z

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Abstract

Unlike inflammatory cell death pathways, apoptosis is a highly regulated process that leads to cell death without the secretion of pro-inflammatory cytokines. The intrinsic apoptosis pathway (IAP) is triggered upon sensing cellular stress, activating pro-death B cell lymphoma 2-associated X (BAX) and B cell lymphoma 2 homologous antagonist killer (BAK) proteins. BAX and BAK induce mitochondrial outer membrane permeabilization (MOMP), spilling cytochrome C (cyt C) into the cytoplasm where it forms the apotosome complex with the apoptotic protease activating factor 1 (Apaf-1). Apaf-1 subsequently induces a cysteine-aspartic protease (caspase) activation cascade culminating in activation of caspases-3/7. Nevertheless, the purpose of the caspase activation cascade remained an interesting conundrum as BAX and BAK, not Apaf-1 and caspases, are necessary for induction of apoptosis. Recent publications seem to indicate that the main function of caspases after activation of apoptosis is to prevent the induction of type I interferons by cyclic GMP-AMP synthase (cGAS) or stimulator of interferon genes (STING) to maintain an immunologically quiescent cell death. I utilized the drug ABT-737 to inhibit the B-cell lymphoma (BCL) family of proteins to prevent the activation of BAK and BAX, leading to MOMP. MOMP causes leakage of cyt C and mitochondrial DNA (mtDNA), activating Apaf-1 and cGAS, respectively. cGAS catalyzes the creation of the cyclic dinucleotide cyclic GMP-AMP (cGAMP) to activate STING which activates downstream targets such as TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) to induce the expression of interferonβ (IFNβ) and interferon-stimulated genes (ISGs) such as C-X-C motif chemokine ligand 10 (CXCL10). However, the mechanism behind caspase-dependent inhibition of the cGAS-STING pathway is currently unknown. My central hypothesis is that caspases-3/7 activate a downstream regulator that inhibits cGAS-mediated cGAMP production. These findings will further our understanding of the regulatory mechanics behind immune responses. As STING is necessary for the production of IFNs downstream of cGAS, it plays an important role in activating the innate immune response during infections. Specifically, mice lacking cGAS or STING are highly susceptible to acute herpes simplex encephalitis (HSE). STING-induced type I IFNs and immune-priming of other cell types were suggested to be critical for protecting mice from HSE. Recent work from our lab has identified an additional primordial downstream pathway of STING: autophagy; in addition, these results indicate that the interferon- and autophagy-inducing function of STING can be uncoupled. To better understand how STING-induced autophagy is controlled, I investigated the necessity of certain canonical autophagy-related genes. To also understand the exact mechanisms downstream of STING activation required for antiviral immunity, I utilized several different STING mutant mice generated in our lab and assessed their response to HSV-1 infection. My results indicate that a novel interferon-independent function of STING was essential to protect against infection and improve the overall survival rates of infected mice; however, STING-induced autophagy was not sufficient to protect against viral challenge.

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