STING, the Endoplasmic Reticulum, and Mitochondria: Is Three a Crowd or a Conversation?

Abstract

The anti-viral pattern recognition receptor STING and its partnering cytosolic DNA sensor cGAS have been increasingly recognized to respond to self DNA in multiple pathologic settings including cancer and autoimmune disease. Endogenous DNA sources that trigger STING include damaged nuclear DNA in micronuclei and mitochondrial DNA (mtDNA). STING resides in the endoplasmic reticulum (ER), and particularly in the ER-mitochondria associated membranes. This unique location renders STING well poised to respond to intracellular organelle stress. Whereas the pathways linking mtDNA and STING have been addressed recently, the mechanisms governing ER stress and STING interaction remain more opaque. The ER and mitochondria share a close anatomic and functional relationship, with mutual production of, and inter-organelle communication via calcium and reactive oxygen species (ROS). This interdependent relationship has potential to both generate the essential ligands for STING activation and to regulate its activity. Herein, we review the interactions between STING and mitochondria, STING and ER, ER and mitochondria (vis-à-vis calcium and ROS), and the evidence for 3-way communication.

Endothelial STING controls Tcell transmigration in an IFN-I dependent manner

“…Double-stranded DNA (dsDNA) activates cytoplasmic DNA sensors that generate cGAMP that directly bind to STING and induce its phosphorylation and translocation to the Golgi-endoplasmic reticulum (endoplasmic-reticulum–Golgi intermediate compartment [ERGIC]). STING associates with TBK-1, IRF3, activated NF-κB and other factors ( 3 ) to form a multimolecular “signalosome” complex that promotes the transcription of IFN-stimulating genes (ISG), such as CXCL10, a chemoattractant for Th1 cells ( 4 – 6 ), and ΝF-κΒ–activated genes ( 7 – 10 ). In humans, gain-of-function mutations in TMEM173 , the gene that encodes for STING, result in S TING- a ssociated v asculopathy with onset in i nfancy (SAVI), an inflammatory disease characterized by upregulated expression of genes associated with the type I IFN (IFNI) pathway ( 11 ).…”

STING controls T cell memory fitness during infection through T cell intrinsic and IDO dependent mechanisms

“…Emerging evidence suggests that ER stress associated with STING activation can elicit apoptosis(41, 42). Under cell stress, the Unfolded Protein Response (UPR) is triggered and chaperone protein Bip dissociates from stress sensors anchored in the ER membrane, leading to the expression of the transcription factor CHOP.…”

Bacterial and metabolic factors of staphylococcal planktonic and biofilm environments differentially regulate macrophage immune activation

“…We could exclude bacterial dsDNA as a STING-inducing factor in our approach, as free DNA content in the CM did not correlate with IFN-β production. Furthermore, we excluded ROS production and oxidative stress, which can result in release of mitochondrial and nuclear DNA into the cytoplasm and subsequent cGAS-mediated STING activation (26,51). Further mechanisms that trigger IFN-β production can be the uptake of extracellular self-DNA released upon cell death and subsequent cGAS-mediated STING activation, activation of STING by bacterial cyclic dinucleotides (CDNs) secreted into the environment (52,53) and the induction of a TLRdepended IFN-β response by SA virulence factors such as protein A (54).…”

“…Free bacterial DNA, however, did not correlate with IFN-β production. Further, STINGmediated IRF-3 activation can be induced by self-DNA release into the cytoplasm upon cell stress via cyclic GMP-AMP synthase (cGAS) (26). As a marker for oxidative stress, we analyzed production of reactive oxygen species (ROS) by macrophages upon stimulation with the CM, but we detected only a slight increase in ROS levels after two hours of stimulation with CM (Fig.…”