Team explores role of STING – stimulator of interferon genes – in body’s innate immunesystem
Provides new insights for treating diseases related to STING inflammation
When pathogens attack the body, the innate immune system goes to work protecting against theinvading disease. The innate immune system is the first line of defense. It detects precisely what
the virus or bacteria is and then activates the proteins that fight the pathogens. Wanting to better
understand how the body’s innate immune system works, a team of scientists undertook a studyof STING, a protein that plays a vital role in innate immunity.
The team provides quantitative results, showing how STING, an acronym for stimulator ofinterferon genes, works in innate immune signaling.
Their work is published in the journal Nature Communications on Jan 11th, 2024.

ER / cis-Golgi network
kinaseactive site

STING(dimer)trans-Golgi network (TGN)TBK1(dimer)

p-IRF3(dimer)

Lipid raft

Phospholipids
PP

Phosphorylation

P

STING translocation
to the TGNcholesterol
sphingomyelin

IRF3PPPPPPP

palmitoylation

A graphical abstract illustrating cholesterol- and palmitoylation-dependent STING clustering at the TGN

Image title: STING clustering at the TGN
Image caption: A graphical illustration of cholesterol- and palmitoylation-dependent STING clustering at the TGN.
Image credit: Institute for Glyco-core Research
Image usage restrictions: News organizations may use or redistribute this image, with proper attribution, as part ofnews coverage of this paper only.

Type I interferons are signaling proteins that respond when they detect the presence of viruses.
They play an essential role in the body’s immune system, communicating between cells as theyfight against pathogens. STING is critical for the type I interferon response to pathogen- or selfderived DNA in the cytosol, the fluid portion of a cell. While STING plays an important role inthe body’s successful protection against infections, dysregulated STING activity leads to theexcessive production of inflammatory mediators that can have a detrimental effect onsurrounding cells and tissues. Recent studies have made the connection between STING and anumber of autoinflammatory and neurodegenerative diseases.
“STING was discovered as a protein that induces innate immune signals in response to virusderived non-self DNA. The STING innate immune response has recently been reported to play
an important role in cancer immune responses and to contribute to inflammatory pathologies inaging, autoinflammatory, and neurodegenerative diseases, making it a highly attractive target for
disease therapy,” said Kenichi G.N. Suzuki, a professor at the Institute for Glyco-core Research,Gifu University and a chief at the Division of Advanced Bioimaging, National Cancer Center
Research Institute.
Research suggests that STING may function as a scaffold to activate the TANK-binding kinase 1(TBK1). TBK1 is a signaling molecule that is activated by receptors when a viral infection
occurs. Scaffold proteins do the important job of regulating key signaling pathways. However, up
to this point, scientists have lacked direct cellular evidence proving that STING activated theTBK1.
To analyze the STING cluster, the research team used a live-cell imaging procedure called
photoactivated localization microscopy or PALM. They performed this single-molecule imagingof STING with enhanced time resolutions down to 5 milliseconds. They determined that STING
becomes clustered at the trans-Golgi network. The trans-Golgi network, or TGN, is a pathway inthe body that directs proteins to the correct subcellular destination.
The team also proved that STING palmitoylation facilitated the STING clustering.
Palmitoylation describes a protein modification process in the body. This palmitoylation ofSTING is required for the cluster formation of STING at the TGN. The Golgi lipid order, alongwith STING palmitoylation, is essential for the STING signaling. The team examined the role ofcholesterol, a lipid that plays an essential role in generating the lipid order in STING’s 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 STING-formed clusters
that activate TBK1 at the TGN.
The team specifically examined the formation of STING clusters as it relates to COPA syndrome.
COPA syndrome is a disorder of immune dysregulation characterized by an increase in type I
interferon-stimulated genes. This autoimmune disorder can impact multiple systems in the body.
The team’s imaging of TBK1 revealed that the increase in the clustering enhances the associationof TBK1. “We provide quantitative proof-of-principle for the signaling STING scaffold, reveal
the mechanistic role of STING palmitoylation in the STING activation, and resolve the longstanding question of the requirement of STING translocation for triggering the innate immunesignaling,” said Tomohiko Taguchi, a professor in the Graduate School of Life Sciences, Tohoku
University.
Looking ahead, the team sees potential for this work helping the fight against disease. “In thepresent study, we showed that inhibition of cholesterol transport to TGN markedly suppressed
the STING innate immune response. Therefore, based on the results of this study, it is expectedthat reducing cholesterol levels will be a new tool to treat the diseases associated with STING
inflammation,” said Suzuki.
Haruka Kemmoku, Kanoko Takahashi, Kojiro Mukai, Yasunori Uchida, Yoshihiko Kuchitsu, andTomohiko Taguchi from Tohoku University; Toshiki Mori, Koichiro M. Hirosawa, and Yasunari
Yokota from Gifu University; Fumika Kiku and Hiroyuki Arai from the University of Tokyo; Yu

Nishioka and Masaaki Sawa from Carna Biosciences, Inc.; Takuma Kishimoto and Kazuma
Tanaka from Hokkaido University; and Kenichi G.N. Suzuki from Gifu University and theNational Cancer Center, Tokyo.
This work was funded by JSPS KAKENHI, JSPS Research Fellowship for Young Scientists,
AMED-PRIME, JST CREST, Subsidy for Interdisciplinary Study and Research concerning
COVID-19 (Mitsubishi Foundation), National Cancer Center Research and Development Fund,Takeda Science Foundation, The Uehara Memorial Foundation, Mizutani Foundation forGlycoscience, Daiichi Sankyo Foundation of Life Science, Research Foundation for OptoScience and Technology, The Naito Foundation, Grant for Basic Science Research Projects fromthe Sumitomo Foundation, SGH Cancer Research Grant, Research Grant of the Princess
Takamatsu Cancer Research Fund, and the Nagoya University CIBoG program from MEXTWISE program.
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Suggested EurekAlert! Summary:When pathogens attack the body, the innate immune system goes to work protecting against theinvading disease. The innate immune system is the first line of defense. It detects precisely what
the virus or bacteria is and then activates the proteins that fight the pathogens. Wanting to better
understand how the body’s innate immune system works, a team of scientists undertook a study ofSTING, a protein that plays a vital role in innate immunity.
###About iGCORE:
Institute for Glyco-core Research (iGCORE) is a cutting-edge integrative glycoscience institutethat brings together researchers from two universities - Nagoya University and Gifu University
under the Tokai National Higher Education and Research System - with outstandingachievements in the fields of glycan synthesis, imaging, glycobiology, and glycomedicine.
Through our research, iGCORE is committed to gaining a deeper understanding of thefundamental nature of life, ultimately paving the way for groundbreaking innovations inmedicine, such as personalized prevention and early detection of pre-disease.
About The National Cancer Center Research Institute:
The National Cancer Center Research Institute is one of the largest cancer research institutions inJapan, with over 350 staff, including postgraduate students and research assistants. The Institutecovers 20 research areas with 9 independent units, as well as the Fundamental Innovative
Oncology Core, established as a common platform serving the entire Center. From highly
original basic research to the development of therapeutic and diagnostic drugs, the Instituteconducts a wide range of activities in collaboration with other units within the Center.
Expert Contact：Kenichi G.N. Suzuki, Ph.D., Professor.
Institute for Glyco-core Research (iGCORE), Gifu University, Gifu, Japan.
Division of Advanced Bioimaging, National Cancer Center Research Institute, Tokyo, Japan.
e-mail: suzuki.kenichi.b7@f.gifu-u.ac.jp
Tomohiko Taguchi, Ph.D., Professor.
Laboratory of Organelle Pathophysiology, Department of Integrative Life Sciences, Graduate
School of Life Sciences, Tohoku University, Sendai, Japan.
e-mail: tomohiko.taguchi.b8@tohoku.ac.jp
Media Contact：
Yutaka Nibu, Ph.D.
Institute for Glyco-core Research (iGCORE), Tokai National Higher Education and ResearchSystem
yutaka.nibu@igcore.nagoya-u.ac.jp