The Emerging Roles of STING in Bacterial Infections

Abstract

The STING (Stimulator of Interferon Genes) protein connects microorganism cytosolic sensing with effector functions of the host cell by sensing directly cyclic dinucleotides (CDNs), originating from pathogens or from the host upon DNA recognition. Although STING activation favors effective immune responses against viral infections, its role during bacterial diseases is controversial, ranging from protective to detrimental effects for the host. In this review, we summarize important features of the STING activation pathway and recent highlights about the role of STING in bacterial infections by Chlamydia, Listeria, Francisella, Brucella, Shigella, Salmonella, Streptococcus, and Neisseria genera, with a special focus on mycobacteria.

Keywords: DNA and nucleotide sensing; STING; Stimulator of Interferon Genes; bacteria; infections.

Figure 1. Schematic model for STING regulation and cytosolic DNA sensing

STING protein is activated by dsDNA or cyclic dinucleotides from pathogens (e.g. c-di-AMP and c-di-GMP). cGAS binds dsDNA to form the cyclic dinucleotide 2′3′ cGAMP which in turn activates STING. Self-DNA, such as mitochondrial DNA, can also be recognized by cGAS. In parallel, other cytosolic DNA sensors like IFI16 are also able to bind dsDNA and activate STING. After this step, the full mechanism of how STING will activate IRF3 or NF-κB is not completely understood. The first hypothesis (A) is that STING moves alone to perinuclear Golgi to bind TBK1, then phosphorylated STING is fully activated. The second postulate (B) is that TBK1 encounters STING directly in the ER, phosphorylating and activating STING at this site, and finally the complex STING-TBK1 moves together to perinuclear Golgi. These two ways lead to IRF3 and NF-κB activation in a perinuclear punctate structure. These transcription factors migrate to the nucleus for activation of type I IFN related genes. Type I IFN response and STING protein need to be regulated to avoid an excessive response involved in several auto-inflammatory diseases (dashed lines). To do that, some regulators like NLRC3, Atg9a and ULK1/Atg1 negatively control STING while ZDHHCI works as a positive regulator. Similarly, there is antagonism between STING and AIM2 inflammasome activation.

Figure 2. Schematic summary of STING activation during M. tuberculosis infection

After entering the cell, M. tuberculosis may elicit STING activation by diverse ways. (A) Mycobacterial DNA or c-di-AMP gain access to the cytosol in an ESX-1-dependent manner. M. tuberculosis DNA is then sensed by cGAS or IFI16, leading to STING activation. Alternatively, M. tuberculosis infection can cause mitochondrial stress, leading to accumulation of mitochondrial DNA in the cytosol and culminating in cGAS-dependent activation of STING pathway. cGAMP produced by cGAS can also pass to bystander cells thanks to GAP junctions. Mycobacterial DNA can also activate AIM2 inflammasome, leading to IL-1β production. (B) After assembly of the STING-TBK1 complex, both host detrimental IFNβ production, through IRF3 activation, and autophagosome assembly, via the recruitment of LC3, may occur.