Cytosolic nucleic acid sensors are critical for sensing nucleic acids and initiating innate immunity during microbial infections and/or cell death. Over the last decade, several key studies have characterized the conserved mechanism of cyclic GMP‒AMP synthase (cGAS) and the downstream signaling adaptor stimulator of interferon genes (STING) initiating the innate immune signaling pathways. Aside from its primary involvement in microbial infections and inflammatory diseases, there is growing interest in the alternate roles of cGAS‒STING-mediated signaling. Caspase family members are powerful functional proteins that respond to cellular stress, including cell death signals, inflammation, and innate immunity. Recent studies have uncovered how the caspase family cooperates with the cGAS‒STING signaling pathway. Most caspase family members negatively regulate the cGAS‒STING signaling pathway. In turn, some caspase family members can also be modulated by cGAS‒STING. This review gives a detailed account of the interplay between the caspase family and the cGAS‒STING signaling pathway, which will shed light on developing novel therapeutics targeting the caspase family and cGAS‒STING signaling in antiviral innate immunity, cancer, inflammatory, and autoimmunity.

The crosstalk between the caspase family and the cGAS‒STING signaling pathway.

As a canonical cytoplasmic DNA sensor, cyclic GMP-AMP synthase (cGAS) plays a key role in innate immunity. In recent years, a growing number of studies have shown that cGAS can also be located in the nucleus and plays new functions such as regulating DNA damage repair, nuclear membrane repair, chromosome fusion, DNA replication, angiogenesis and other non-canonical functions. Meanwhile, the mechanisms underlying the nucleo-cytoplasmic transport and the regulation of cGAS activation have been revealed in recent years. Based on the current understanding of the structure, subcellular localization and canonical functions of cGAS, this review focuses on summarizing the mechanisms underlying nucleo-cytoplasmic transport, activity regulation and non-canonical functions of cGAS in the nucleus. We aim to provide insights into exploring the new functions of cGAS in the nucleus and advance its clinical translation.

cGAS: action in the nucleus

Bovine tuberculosis is a chronic infectious disease primarily caused by Mycobacterium bovis, a bacterium that affects cattle and other mammals, including humans. Despite the availability of vast research about the immune response mechanisms of human tuberculosis caused by Mycobacterium tuberculosis, the knowledge of bovine tuberculosis’s immunology, particularly regarding the innate immune response, still remains scarce. In this study, we compared the transcriptome of cell cultures containing lymphocytes and M. bovis infected-macrophages with two strains of variable virulence, the virulent Mb04-303 strain and the attenuated Mb534. To that end, we infected bovine macrophages at a multiplicity of infection of one, and co-cultured the infections with autologous lymphocytes. RNA obtained from the co-cultures was sequenced to identify differentially expressed gene pathways by using the database Reactome. The RNA-seq analysis showed that the Mb04-303 infection upregulated the type 1 interferon signalling pathway, while it downregulated the KEAP1-NFE2L2 pathway. According to the literature, this last pathway is involved in the activation of antioxidant genes and inflammasome. In addition, the macrophages infected with Mb04-303 recruited more Galectin 8 than those infected with Mb534. This result indicates that Mb04-303 induced higher phagosome membrane damage, with the possible concomitant release of bacterial compounds into the cytoplasm that activates the type I signalling pathway. Altogether, Mb04-303 repressed the antioxidant and anti-inflammatory responses, likely impairing interleukin-1β activation, and trigged the canonical type 1 interferon signalling. Although these responses led to the control of bacterial replication during early infection, the virulent strain eventually managed to establish a successful infection.

A Transcriptional Analysis of Cattle Immune Cells Reveals a Central Role of Type 1 Interferon in the In Vitro Innate Immune Response against Mycobacterium bovis

As a gram-negative intracellular bacterial pathogen, Salmonella enterica serovar Typhimurium (S. Typhimurium) invades different cell types including macrophages. Its infection in macrophages induces robust innate immune responses that are featured by proinflammatory and type I interferon (IFN) responses. The type III secretion systems (T3SSs) of S. Typhimurium play a crucial role in activating host inflammasome pathways. It has been recognized that the inflammasome pathways inhibit the type I IFN cascade. However, the potential role of T3SS in regulating the type I IFN response and the underlying mechanisms are largely unknown. In this study, we showed that S. Typhimurium infection activated strong proinflammatory, type I IFN and IFN-stimulated genes (ISGs) expression in macrophages. Furthermore, we showed that T3SS-defective S. Typhimurium mutant ΔinvC elicited attenuated inflammatory response but enhanced type I IFN and ISGs expression. Additionally, the inhibition of caspase-1 by a specific inhibitor VX-765 resulted in increased type I IFN response. Moreover, cell-permeable pan-caspase inhibitor Z-VAD-FMK also enhanced the type I IFN response upon S. Typhimurium infection. Intriguingly, compared with exponential phase S. Typhimurium infection, stationary phase bacteria triggered higher levels of type I IFN responses. Finally, the inhibition of caspase-1 by VX-765 substantially increased the intracellular S. Typhimurium burden. In conclusion, we demonstrated that the proinflammatory response induced by S. Typhimurium T3SS can inhibit the type I IFN response, which provides insight into the role of T3SS in orchestrating innate immunity during S. Typhimurium infection. 

Salmonella T3SS-elicited inflammatory innate immune response inhibits type I IFN response in macrophages

Abstract The cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway senses double-stranded DNA in the cytoplasm, triggering the secretion of type I and III interferons and proinflammatory cytokines. However, cGAS–STING pathway activation by STING agonists also induces regulated cell death (RCD) in human monocytes, which is inherently linked to cytokine production. We identified that STING agonist-induced monocyte RCD integrates apoptotic (active caspase-9, -8 and -3/7) and pyroptotic mechanisms (active caspase-1, cleaved gasdermin-D and secreted mature interleukin-1β and -18), whereas necroptosis is inhibited through caspase-8-mediated cleavage of receptor-interacting protein kinase 1 (RIPK1). Additionally, this RCD is accompanied by mitochondrial dysfunction, which precedes caspase activation, suggesting that mitochondrial disruption may act as both the driving mechanism and a direct outcome of cGAS–STING pathway activation via the STING–IRF3–BAX pathway. Overall, this study identifies a novel RCD process that may be described as ‘pyroptotic apoptosis’, providing new insights into the outcomes of cGAS–STING signalling in human monocytes. 

pdf/sting-agonists-trigger-monocyte-death-via-apoptosis-a38zld37ip8m.pdf

STING agonists trigger monocyte death via apoptosis, pyroptosis, caspase-8 activation and mitochondrial dysfunction

Caspase-1 inhibits IFN-β production via cleavage of cGAS during M. bovis infection.

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Caspase-1 inhibits IFN-β production via cleavage of cGAS during M. bovis infection.