Molecular and spatial mechanisms governing STING signalling

Abstract

Detection of microbial nucleic acids via innate immune receptors is critical for establishing host defence against pathogens. The DNA-sensing cGAS-STING pathway has gained increasing attention in the last decade as a key pathway for combating viral and bacterial infections. cGAS-STING activation primarily promotes the secretion of antiviral type I IFNs via the key transcription factor, IRF3. In addition, cGAS-STING signalling also elicits pro-inflammatory cytokines through NF-B activity. Activation of IRF3 and NF-B is mediated by the chief signalling receptor protein STING. Interestingly, STING undergoes significant trafficking events across multiple subcellular locations, which regulates both the activation of downstream signalling pathways, as well as appropriate termination of the responses. Studies to date have provided a comprehensive view of the regulation and role of the IRF3-IFN pathway downstream of STING. However, many aspects of STING signalling remain relatively poorly defined. This review will explore the current understanding of the mechanisms through which STING elicits inflammatory and antimicrobial responses, focusing on the precise signalling and intracellular trafficking events that occur. We will also discuss exciting and emerging concepts in the field, including the importance of IFN-independent STING responses for host defence and during STINGrelated disease.

Self-DNA Sensing by cGAS-STING and TLR9 in Autoimmunity: Is the Cytoskeleton in Control?

“…Proteins and mechanisms involved in movements of cGAS-STING across intracellular compartments are being increasingly elucidated and illustrate the critical role of trafficking for signal regulation [reviewed in ( 64 )]. STIM1 is an ER-resident Ca2 + binding protein implicated in replenishing Ca2 + stores at ER-plasma membrane (ER-PM) contact sites.…”

The Key Role of NAD+ in Anti-Tumor Immune Response: An Update

“…Recent studies showed that some purinergic ectoenzymes metabolize cyclic dinucleotides, such as 2',3'cyclic GMP-AMP (cGAMP) (21). CD203a/ENPP1 metabolizes cGAMP generating AMP and GMP (22). cGAMP is an activator of the stimulator of interferon genes (STING), which stimulate innate immunity.…”

“…Links between the cGAS-STING pathway with CD203a/ENPP1 and NAD + have recently emerged whereby the hydrolysis of cGAMP by CD203a/ENPP1 attenuates cGAS-STING signaling and NAD + cleavage (23,24). Indeed, bacterial STING, containing a NADase-TIR domain, recognizes cyclic dinucleotides in a conformation similar to cGAMP in complex with human STING, allowing for b-NAD + hydrolysis (22). NAD + cleavage activity of bacterial TIR domains is conserved in the mammalian SARM1 (sterile alpha and TIR motif containing 1) NAD + -glycohydrolase (23,25).…”

Type-I Interferon Signaling in Fanconi Anemia

“…Then, cGAMP acts as a secondary messenger to activate the Stimulator of Interferon Genes (STING), inducing its conformational change and subsequent activation (Ablasser et al, 2013;Wu et al, 2013;Sun et al, 2013). In its activated form, STING interacts with Tank-binding Kinase I (TBK1) and the IKK complex to activate them, which leads to STING phosphorylation by TBK1, then recruitment and activation of IRF3 followed by the release of Nuclear Factor-kappaB (NF-kB), ultimately promoting the production of IFN-I and other inflammatory cytokines (Balka and De Nardo, 2021). During acute immune responses, IFN-I activation is usually beneficial to the host by providing transcriptional changes that allow the orchestration of an efficient response.…”