Activation of STING due to COPI-deficiency

Abstract

<jats:p>COPA syndrome is caused by loss-of-function mutations in the COP-α subunit of coatomer protein complex I (COPI), which participates in retrograde vesicular trafficking of proteins from the Golgi to the endoplasmic reticulum (ER). Disease manifests early in life with arthritis, lung pathology, kidney dysfunction and systemic inflammation associated with NF-κB activation and type I interferon (IFNαβ) production. Here, we generated in vitro models for COPA syndrome and interrogated inflammatory signalling pathways via a range of biochemical and molecular biological techniques. Results were confirmed with cell lines in which mutant COPA was overexpressed and with COPA syndrome patient PBMCs. We identified Stimulator of Interferon Genes (STING), as a driver of inflammation in COPA syndrome. Furthermore, we found that genetic deletion of COPG1, another COPI subunit protein, induced NF-κB and type I IFN pathways similar to COPA-deficiency. Finally, we demonstrate that in vitro, inflammation due to COPA syndrome mutations was ameliorated by treatment with the small molecule STING inhibitor H-151. Therefore, inflammation induced by deletion of COPI subunits in general suggests a link between retrograde trafficking and STING regulation, and this innate immune sensor represents a novel therapeutic target in COPA syndrome.</jats:p>

CDK inhibitor Palbociclib targets STING to alleviate autoinflammation

“…In our study, we have identified STING as a novel target of Palbociclib. It has been well documented that STING plays a crucial role in promoting anti‐tumor immunity by activating innate immunity, boosting DC maturation (Curran et al , 2016) and activating natural killer cells (Nicolai et al , 2020; preprint: Steiner et al , 2020) as well as CD8 + T cells (Sen et al , 2019). It is, therefore, highly likely that CDKi‐mediated inhibition of STING activation may impair STING‐mediated anti‐tumor immunity, which will bring attention to potential drawbacks in the clinical application of Palbociclib and its structural analogs in cancer therapy.…”

Inhibitory targeting cGAS-STING-TBK1 axis: Emerging strategies for autoimmune diseases therapy

“…Nerveless, cGAS inhibitors still can be a good complement to therapeutic regimens for the treatment of DNA-dependent autoimmune diseases. Besides, it was reported that TBK1 inhibitor BX795 could downregulate IFN-I activation in PBMCs of SS, SLE, and MS patients ( 183 , 184 ). Compared to blocking common natural immune targets, such as TBK1 or IFNs, inhibition of cGAS-STING has less risk of immunosuppression and opportunistic infections without keeping the other PRR systems intact.…”

Viperin binds STING and enhances the type‐I interferon response following dsDNA detection

“…The STING knockout cell line was a kind gift from Annemarie Steiner (Walter and Eliza Hall Institute of Medical Research, Parkville, Australia) and were generated using CRISPR/Cas9 gene editing as described previously 59 . In brief, gene deletion was induced in stably Cas9‐expressing HeLa cells by treatment of doxycycline (1 µg mL −1 , Sigma‐Aldrich) for 72 h to induce expression of STING ‐targeting sgRNA.…”