DALLAS – UT Southwestern Medical Center – April 6, 2022 – Photography at close proximity to the atomic solution of a protective protein commonly known as STING has revealed an unprecedented binding site that appears to be important in launching an antibody attack, reports UT Southwestern scientists in a new study. The findings, published in Nature, could lead to new ways of exploiting STING in order to stimulate strong immune responses or inhibit its action in autoimmune diseases.
“For the first time, this work provides an accurate picture of STING’s activated condition, which is important in understanding its role in both the immune system and autoimmune diseases,” said study author Xuewu Zhang, Ph.D., Professor of Pharmacology and Autoimmune Disease I -Biophysics at UT Southwestern. Drs. Zhang led joint research with Xiaochen Bai, Ph.D., Associate Professor of Biophysics and Cell Biology at UT Southwestern, and his postdoctoral colleagues Defen Lu and Guijun Shang. Drs. Zhang and Drs. They are members of the Harold C. Simmons Comprehensive Cancer Center.
STING, translated as “interferon genetic stimulant,” is a major component of the immune system, which acts as the first line of defense against viruses, bacteria, and cancer. After a cGAS sensor receives foreign DNA from cells, it produces a messenger molecule known as the cyclic GMP-AMP (cGAMP) that activates STING. Next, STING introduces a number of signaling pathways that promote the production of inflammatory molecules and chemical signals that encourage cells to clear detritus to eliminate invaders.
In collaboration with UT Southwestern researcher Zhijian “James” Chen, Ph.D., Professor of Molecular Biology and Center for Genetics of Host Defense, Zhang’s lab and Bai lab previously reported the first images of -STING taken with cryogenic electron microscopy (cryo-EM), a method that makes proteins freeze in place to accurately assess their structure, at UTSW’s Cryo-Electron Microscopy Facility.
Although this work has clarified some of the key mechanisms that regulate STING activity, how this protein transforms into an active form was not yet clear. To answer that question, Zhang and Bai labs mix pure STING proteins with cGAMP and use cryo-EM to represent the resulting product. However, the researchers saw a number of STING molecules activated, and the existing ones were unstable.
In hopes of increasing the amount of activated STING found in the image, scientists have added an investigative drug known as compound 53 (C53) which is currently being tested as a STING anti-cancer treatment activist. C53 was thought to bind to the same location as cGAMP in STING.
The combination of cGAMP and C53 produced highly active STING molecules. But when researchers looked for C53 in cryo-EM images, they found it in a completely different environment than cGAMP, ultimately the opposite molecule.
“This newly discovered binding site for STING operations came as a surprise,” explains Drs. Bai. We call it the ‘cryptic pocket’ because it seems to build up due to the presence of the C53. There is no proof of this site without the C53. ”
The fact that STING appears to require both cGAMP and C53 to function efficiently and steadily suggests that an unknown molecule such as C53 may be present in cells to fill a similar role, said Drs. Zhang. Future research will focus on finding this molecule and better understanding its function.
One day, researchers added, drugs that adhere or block the newly discovered site could be used to strengthen or reduce infection to fight infectious or autoimmune diseases.
Jie Li and Yong Lu from UT Southwestern also contributed to the study.
Drs. Zhang and Bai are both experts at the Virginia Murchison Linthicum in medical research. Drs. Chen holds the Honorary Chair of George L. MacGregor in Biomedical Science and is a researcher at the Howard Hughes Medical Institute.
This work is funded in part by grants from the National Institutes of Health (R35GM130289 and R01GM143158), the Welch Foundation (1702 and 1944) and the Cancer Prevention and Research Institute of Texas (RP160082)
