A graphical illustration of cholesterol-dependent STING clustering and palmitoylation at the TGN. Credit: Glyco-core Research Institute
When pathogens attack the body, the innate immune system goes to work to protect it against the invading disease. The innate immune system constitutes the first line of defense. It detects precisely what the virus or bacteria is and then activates proteins that fight pathogens. Wanting to better understand how the body’s innate immune system works, a team of scientists undertook a study of STING, a protein that plays an essential role in innate immunity.
The team provides quantitative results showing how STING, short for stimulator of interferon genes, acts in innate immune signaling.
Their work is published in the journal Natural communications on January 11, 2024.
Type I interferons are signaling proteins that respond when they detect the presence of viruses. They play a vital role in the body’s immune system, communicating between cells in their fight against pathogens.
STING is essential for the type I interferon response to pathogenic or self-derived DNA in the cytosol, the fluid part of a cell. While STING plays an important role in effectively protecting the body against infections, dysregulated STING activity leads to excessive production of inflammatory mediators that can have a detrimental effect on surrounding cells and tissues.
Recent studies have linked STING to a number of autoinflammatory and neurodegenerative diseases.
“STING was discovered as a protein that induces innate immune signals in response to virus-derived non-self DNA. The STING innate immune response has recently been reported to play an important role in cancer immune responses and contribute “aging-related inflammatory pathologies, auto-inflammatory and neurodegenerative diseases, making it a very attractive target for disease treatment,” said Kenichi GN Suzuki, professor at the Glyco-core Research Institute, Gifu University and head of the Division of Advanced Bioimaging, National Cancer Center Research Institute. .
Research suggests that STING may function as a scaffold to activate TANK-binding kinase 1 (TBK1). TBK1 is a signaling molecule activated by receptors when a viral infection occurs. Scaffolding proteins do the important work of regulating key signaling pathways. However, until now, scientists lacked direct cellular evidence that STING activates TBK1.
To analyze the STING cluster, the research team used a live-cell imaging procedure called photoactivated localization microscopy, or PALM. They achieved this single-molecule imaging of STING with improved temporal resolutions of up to 5 milliseconds. They determined that STING was clustering on the trans-Golgi network. The trans-Golgi network, or TGN, is a pathway in the body that directs proteins to the correct subcellular destination.
The team also showed that palmitoylation of STING facilitated STING clustering. Palmitoylation describes a process of modifying proteins in the body. This palmitoylation of STING is necessary for the formation of STING clusters at the TGN. Golgi lipid ordering, as well as STING palmitoylation, is essential for STING signaling. The team examined the role of cholesterol, a lipid that plays a critical role in generating lipid order in STING signaling and clustering.
They used a cholesterol biosensor and an environmentally sensitive probe for lipid membranes, to further demonstrate that cholesterol plays a role in the palmitoylated groups formed by STING that activate TBK1 at the TGN.
The team specifically examined the formation of STING groups as it relates to COPA syndrome. COPA syndrome is an immune dysregulation disorder characterized by an increase in genes stimulated by type I interferon. This autoimmune disease can affect multiple systems in the body.
The team’s imaging of TBK1 revealed that increased clustering enhances TBK1 association. “We provide quantitative proof of principle for the STING signaling scaffold, reveal the mechanistic role of STING palmitoylation in STING activation, and resolve the long-standing question of whether STING translocation is required to trigger signaling. innate immune system,” Tomohiko said. Taguchi, professor at the Graduate School of Life Sciences at Tohoku University.
Looking ahead, the team sees the potential of this work in fighting disease. “In the present study, we showed that inhibition of cholesterol transport to the TGN markedly suppressed the STING innate immune response. Therefore, based on the results of this study, it is expected that reducing cholesterol levels will be a new tool to treat related diseases. with STING inflammation,” Suzuki said.
More information:
Haruka Kemmoku et al, Single-molecule localization microscopy reveals STING clustering at the trans-Golgi network through palmitoylation-dependent cholesterol accumulation, Natural communications (2024). DOI: 10.1038/s41467-023-44317-5
Provided by Tokai National Higher Education and Research System
Quote: Team explores role of ‘interferon gene enhancer’ in body’s innate immune system (January 12, 2024) retrieved January 12, 2024 from
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