When pathogens invade the body, the innate immune system will play a role in resisting the invading pathogens. The innate immune system is the first line of defense. It can accurately detect viruses or bacteria, and then activate proteins to fight against pathogens. In order to better understand the working principle of the innate immune system in the body, researchers from research institutions such as the National Cancer Center Research Institute, Tohoku University, and Gifu University in Japan conducted a new study on STING, a protein that plays an important role in innate immunity. Their research findings demonstrate how STING plays a role in innate immune signaling. The relevant research results were published in the journal Nature Communications, with the title “Single-molecule localization microscopy reveals STING clustering at the trans-Golgi network through palmitoylation-dependent accumulation of cholesterol”.

 

Type I interferon is a signaling protein that reacts when the presence of a virus is detected. They play an important role in the human immune system, communicating between cells in the fight against pathogens.

 

STING is crucial for the response of type I interferon to pathogens or self-generated DNA in the cytoplasm (liquid part of cells). STING plays an important role in the body’s successful defense against infection, but dysfunction of STING activity can lead to excessive production of inflammatory mediators, which can have harmful effects on surrounding cells and tissues.

 

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Recent studies have found that STING is associated with various autoimmune and neurodegenerative diseases. According to Kenichi G.N. Suzuki, co-author of the paper and professor at the Institute of Sugar Core Studies at Gifu University, “STING has been discovered as a protein that can induce innate immune signals as a response to non-self DNA derived from viruses. Recently, reports have shown that STING’s innate immune response plays an important role in cancer immune response and leads to inflammatory pathological changes in aging, autoimmune inflammation, and neurodegenerative diseases, making it an attractive target for disease treatment.”

 

Previous studies have shown that STING may act as a scaffold protein to activate TANK binding kinase 1 (TBK1). TBK1 is a signaling molecule that is activated by receptors when infected with a virus. Scaffold proteins play an important role in regulating key signaling pathways. However, so far, scientists have not had direct cellular evidence to confirm that STING activates TBK1.

 

To analyze STING aggregates, these authors used a live cell imaging program called photoactivated localization microscopy (PALM). They performed single molecule imaging on STING, with a time resolution increased to 5 milliseconds. They found that STING aggregates in the Trans-Golgi network (TGN). TGN is the pathway in the human body that directs proteins to the correct subcellular destination.

 

These authors also confirmed that STING palmitoylation promotes STING aggregation. Palmitoylation describes a protein modification process in the human body. The palmitoylation of STING is necessary for the formation of aggregates in TGN. The lipid order of the Golgi apparatus and STING palmitoylation are crucial for STING signal transduction. They studied the role of cholesterol as a lipid, which plays a crucial role in the generation of lipid order during STING signal transduction and STING aggregate formation.

 

 

They further confirmed the role of cholesterol in the aggregates formed by palmitoylation STING using cholesterol biosensors and environmentally sensitive lipid membrane probes, which can activate TBK1 in TGN.

 

These authors specifically investigated the relationship between the formation of STING aggregates and COPA syndrome. COPA syndrome is an immune dysregulation characterized by an increase in type I interferon-stimulated genes. This autoimmune disease can affect multiple systems in the body.

 

The imaging of TBK1 by these authors showed that the increase of STING aggregates enhanced the binding with TBK1. Tomohiko Taguchi, co-author of the paper and professor of life sciences at the Graduate School of Northeastern University, said, “We provide a quantitative proof of principle for STING signaling scaffolds, revealing the mechanism of STING palmitoylation in STING activation, and solving the long-standing problem of STING translocation triggering innate immune signals.”

 

These authors believe that this new study has the potential to help people fight against diseases. “In this new study, we found that inhibiting the transport of cholesterol to TGN significantly suppressed STING innate immune response. Therefore, according to the results of this study, reducing cholesterol levels is expected to become a new tool for treating STING inflammation-related diseases.”

 

Reference

Haruka Kemmoku et al. Single-molecule localization microscopy reveals STING clustering at the trans-Golgi network through palmitoylation-dependent accumulation of cholesterol. Nature Communications, 2024, doi:10.1038/s41467-023-44317-5.