The interactions between cGAS-STING pathway and pathogens

Abstract

Cytosolic DNA is an indicator of pathogen invasion or DNA damage. The cytosolic DNA sensor cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) detects DNA and then mediates downstream immune responses through the molecule stimulator of interferon genes (STING, also known as MITA, MPYS, ERIS and TMEM173). Recent studies focusing on the roles of the cGAS-STING pathway in evolutionary distant species have partly sketched how the mammalian cGAS-STING pathways are shaped and have revealed its evolutionarily conserved mechanism in combating pathogens. Both this pathway and pathogens have developed sophisticated strategies to counteract each other for their survival. Here, we summarise current knowledge on the interactions between the cGAS-STING pathway and pathogens from both evolutionary and mechanistic perspectives. Deeper insight into these interactions might enable us to clarify the pathogenesis of certain infectious diseases and better harness the cGAS-STING pathway for antimicrobial methods.

Fig. 1

The cGAS-STING pathway. The presence of cytosolic DNA is an indicator of pathogen invasion. Cytosolic DNA is sensed by cGAS, resulting in the formation of cGAS-DNA liquid droplets, in which cGAS, ATP, and GTP are concentrated to powerfully enhance the production of cGAMP. STING binding to cGAMP undergoes conformational changes, leading to the release of C-terminal tails (CTT) and polymerization. Polymerized STING translocates from the ER to Golgi via ERGIC, where STING initiates the autophagy process, which contributes to the clearance of cytosolic DNA and pathogens. During the translocation process, STING also recruits TBK1. Recruited TBK1 undergoes trans-autophosphorylation and then phosphorylates STING in its CTT. Phosphorylated STING recruits IRF3 for phosphorylation and activation by TBK1. In addition to IRF3, TBK1 also activates NF-κB and STAT6. These activated transcriptional factors would translocate into the nucleus and induce the expression of various immunomodulatory genes, such as IFNβ and IL-6, leading to the establishment of an antipathogen state. After the translocation process, STING would be targeted to the lysosome for degradation to avoid overimmunization

Fig. 2

Evolution of the cGAS-STING pathway. a Comparison of the functional domains in cGAS and STING between invertebrate (anemone) and vertebrate (human) species. Compared with human cGAS, anemone cGAS has a shorter N terminal and lacks the zinc-ribbon finger, both of which are involved in DNA binding in vertebrate cGAS. The C-terminal tail, which is essential for IFN induction in vertebrate STING, is also absent in anemone STING. b Currently identified cGAS-STING pathway in different species. While the cGAS-STING pathways in different species share a similar framework, there are two notable observations: firstly, no studies have suggested that invertebrate cGAS could detect DNA as vertebrate cGAS do, and the function of invertebrate cGAS remains unclear; secondly, the cGAS-STING pathway seems to have acquired more antipathogen methods during evolution

Fig. 3

Multiple detection strategies against pathogens. The dynamic regulations of cGAS activity, the wide intracellular distributions of cGAS, and the cell cooperative detection of pathogens constitute several layers of pathogen detection. In addition to the presence of PAMPs, other information indicating pathogen invasion, including the activation of cGAS coaction proteins and the emergence of danger-associated signals, can be integrated into pathogen detection. Multilayered pathogen detection and the capacity of integrating various information render the cGAS-STING pathway with unique sensitivity to infection to initiate a series of antipathogen responses

Fig. 4

Post-translational modifications of cGAS and STING. This figure illustrates the post-translational modifications of cGAS and STING in resting states upon viral infection, which serve to restrict the activity of the cGAS or STING after activation. A acetylation, E glutamylation, P phosphorylation, Ub ubiquitination, S sumoylation, K11-(Ub)n K11-linked polyubiquitination, K27-(Ub)n K27-linked polyubiquitination, K48-(Ub)n K48-linked polyubiquitination, K63-(Ub)n K63-linked polyubiquitination

Fig. 5

Pathogen evasions from cGAS-STING pathway. Different strategies are adopted by HSV-1 and HIV-1 to evade from the surveillance of the cGAS-STING pathway. Whereas HSV-1 mainly encodes a variety of proteins to counter key signal transduction processes of the cGAS-STING pathway, HIV-1 utilizes cellular autonomous restriction factors and transport systems to limit exposure of its viral DNA to cGAS. The viral proteins encoded by HSV-1 are shown in the same colour as HSV-1 capsids