In new research, UT Southwestern scientists report that imaging a key immunity protein known as STING at near-atomic resolution reveals a previously undiscovered binding location that appears to be crucial for launching immunological attacks.
The discoveries, which were published in Nature, could lead to novel techniques to manipulate STING to boost immune responses or prevent it from acting in autoimmune illnesses.
For the first time, this work provides a precise picture of the activated state of STING, critical for understanding its role in both normal immunity as well as autoimmune diseases.”
Xuewu Zhang, PhD, Study Author and Professor, Pharmacology and Biophysics, UT Southwestern Medical Center
Dr Zhang co-led the research with UT Southwestern’s Xiaochen Bai, PhD, Associate Professor of Biophysics and Cell Biology, and postdoctoral scholars Defen Lu and Guijun Shang. The Harold C. Simmons Comprehensive Cancer Center is home to Dr Zhang and Dr Bai.
The innate immune system, also known as STING, is the body’s initial line of defense against viruses, bacteria, and malignancies. When a sensor called cGAS recognizes foreign DNA in cells, it produces cyclic GMP-AMP (cGAMP), a messenger molecule that stimulates STING.
As a result, STING activates several signaling pathways that promote the creation of inflammatory chemicals as well as chemical signals that tell cells to clean up trash to eradicate invaders.
The Zhang lab and Bai lab initially demonstrated the first images of STING taken with cryogenic electron microscopy (cryo-EM), a method that seals proteins in place to properly estimate their structure, in UTSW’s Cryo-Electron Microscopy Facility, in collaboration with UT Southwestern researcher Zhijian “James” Chen, PhD, Professor of Molecular Biology and the Center for Genetics of Host Defense.
Although this research revealed some of the basic factors that regulate STING activity, it is still unclear how this protein shifts from a dormant to an active state. To find an answer, the Zhang and Bai labs combined pure STING protein with cGAMP and imaged the resultant product using cryo-EM. The researchers, on the other hand, found few active STING molecules, and those that were found were unstable.
To boost the quantity of active STING available for imaging, the researchers added compound 53 (C53), an experimental medication currently being evaluated as a STING activator for anti-cancer therapy. On STING, C53 was thought to bind to the same location as cGAMP.
STING molecules were substantially more activated when cGAMP and C53 were combined. However, when the researchers examined cryo-EM pictures for C53, they discovered it in a completely different location than cGAMP, at the molecule’s opposite end.
This newly discovered binding site for STING activation came as a complete surprise. We call it a ‘cryptic pocket’ because it appears to form in response to the presence of C53. No evidence of this site exists when C53 is absent.”
Xiaochen Bai, PhD, Associate Professor, Biophysics and Cell Biology, UT Southwestern Medical Center
The fact that STING appears to require both cGAMP and C53 to become highly and permanently activated suggests that a molecule similar to C53 may occur in cells to perform the same function, according to Dr Zhang. The quest for this molecule and a better understanding of its function will be the focus of future studies.
Drugs that connect to or block this newly found binding site could one day be utilized to enhance or depress immunity in the battle against viral or autoimmune disorders, according to the researchers.
UT Southwestern’s Jie Li and Yong Lu also contributed to this research.
Dr Zhang and Dr Bai are Virginia Murchison Linthicum Medical Research Scholars. Dr Chen is a Howard Hughes Medical Institute Investigator and possesses the George L. MacGregor Distinguished Chair in Biomedical Science.
Lu, D., et al. (2022) Activation of STING by targeting a pocket in the transmembrane domain. Nature. doi.org/10.1038/s41586-022-04559-7.