Abstract
Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS), along with the adaptor stimulator of interferon genes (STING), are crucial components of the innate immune system, and their study has become a research hotspot in recent years. Many biochemical and structural studies that have collectively elucidated the mechanism of activation of the cGAS-STING pathway with atomic resolution have provided insights into the roles of the cGAS-STING pathway in innate immunity and clues to the origin and evolution of the modern cGAS-STING signaling pathway. The cGAS-STING pathway has been identified to protect the host against viral infection. After detecting viral dsDNA, cGAS synthesizes a second messenger to activate STING, eliciting antiviral immune responses by promoting the expression of interferons (IFNs) and hundreds of IFN-stimulated genes (ISGs). Recently, the cGAS-STING pathway has also been found to be involved in response to bacterial infections, including bacterial pneumonia, melioidosis, tuberculosis, and sepsis. However, compared with its functions in viral infection, the cGAS-STING signaling pathway in bacterial infection is more complex and diverse since the protective and detrimental effects of type I IFN (IFN-I) on the host depend on the bacterial species and infection mode. Besides, STING activation can also affect infection prognosis through other mechanisms in different bacterial infections, independent of the IFN-I response. Interestingly, the core protein components of the mammalian cGAS-STING signaling pathway have been found in the bacterial defense system, suggesting that this widespread signaling pathway may have originated in bacteria. Here, we review recent findings related to the structures of major molecules involved in the cGAS-STING pathway and the effects of the cGAS-STING pathway in various bacterial infections and bacterial immunity, which may pave the way for the development of new antibacterial drugs that specifically kill bacteria without harmful effects on the host.
Highlights
Bacterial infections caused by opportunistic pathogens or invading pathogenic bacteria are the major infectious diseases worldwide, causing many diseases, including pneumonia, periodontitis, tuberculosis, conjunctivitis, gastroenteritis, and sepsis [1,2,3,4,5]
M. tuberculosis coding protein Rv0753c (MmsA) can decrease stimulator of interferon genes (STING) levels and subsequent interferon regulatory factor 3 (IRF3) activation by binding and colocalizing with STING, and facilitate STING autophagic degradation by binding with p62, resulting in the inhibition of STING-TBK1IRF3 pathway [130]; M. tuberculosis phosphodiesterase (PDE) can inhibit STING activation by cleaving both c-di-adenosine monophosphate (AMP) and cGAMP to blunt the antibacterial response [133]; M. tuberculosis isolates associated with severe tuberculosis can evade cGASSTING surveillance system by accumulating mutations in the ESX components or generating sigA recognition boxes, and at the same time, IL-1b secretion caused by these isolates is significantly decreased [131]
A series of studies in cytosolic surveillance systems have made fruitful progress and demonstrated a critical role of the cGAS-STING signaling pathway in bacterial infection. Both extracellular and intracellular bacteria activate cGASSTING signaling in host cells through PAMPs, including bacterial DNA, CDNs, and LPS, or DAMPs, such as cytosolic DNA released from host mitochondria and the nucleus
Summary
Bacterial infections caused by opportunistic pathogens or invading pathogenic bacteria are the major infectious diseases worldwide, causing many diseases, including pneumonia, periodontitis, tuberculosis, conjunctivitis, gastroenteritis, and sepsis [1,2,3,4,5]. Unlike the case in viruses, bacterial lipopolysaccharide (LPS) and cyclic di-nucleotides (CDNs, including c-di-AMP, c-diGMP, 2’2’-cGAMP, and 3’3’-cGAMP) can activate the cGASSTING pathway, in addition to bacterial DNA [30,31,32,33,34,35] Both extracellular CDNs (eCDNs) and intracellular CDNs (iCDNs) can activate STING independently of cGAS to initiate the host immune response (Figure 1), while recent studies have found that cGAS facilitates sensing of eCDNs to activate innate immunity [36]. It is likely that closure of the ligandbinding domain is not required for STING activation but is beneficial for increasing binding affinity [50] Another conformational change induced by cGAMP is that the LBD of STING rotates 180° relative to the TM domain, causing the two connector LBDa1 elements, which form a right-handed crossover in the apo state, to become parallel to each other [52]. The interaction between the cGAS-STING pathway and gram-positive or gram-negative bacteria will be discussed in detail below (Table 1 and Figure 3)
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