Immune protein STING key for repairing, generating lysosomes
UTSW researchers’ findings could lead to new treatments for some neurodegenerative diseases
DALLAS – April 14, 2025 – The STING protein, known for helping cells fight viral infections by generating inflammation, also appears to function as a quality control sensor for organelles that serve as cellular waste disposal systems, UT Southwestern Medical Center researchers found. Their study, published in Molecular Cell, helps explain critical features of diseases called lysosomal storage disorders and could eventually lead to new treatments for these and other neurodegenerative diseases.
“STING is well known as an innate immune signaling protein. This study uncovered a new nonimmune function of STING,” said study leader Nan Yan, Ph.D., Professor and Vice Chair of Immunology and Professor of Microbiology at UT Southwestern.
There are more than 70 known lysosomal storage disorders (LSDs). These rare neurodegenerative diseases are characterized by the dysfunction of lysosomes, cellular organelles that break down various substances ready for disposal, including proteins, nucleic acids, and even other organelles, by digesting them in acid. This dysfunction allows substances that would normally be broken down to accumulate to harmful levels.
Inflammation in the nervous system is a prevailing symptom of these disorders. But why lysosomal dysfunction causes neuroinflammation has been unclear. In a 2021 study, Dr. Yan and colleagues showed that STING – short for stimulator of interferon genes – drives this symptom for one LSD, Niemann-Pick disease type C1 (NPC1).
To see whether STING is involved in other LSDs, Dr. Yan’s team at UTSW worked with a mouse model of an LSD called Krabbe disease with the same mutation found in human disease. In some of these animals, the researchers also deleted the gene for STING. Compared with animals that carried neither genetic defect, those with only the Krabbe mutation had a substantial increase in the activity of inflammatory genes, particularly in a type of nervous system cell called microglia. Consequently, they developed severe neuroinflammation by about a month of age. However, in those also missing the STING gene, this increased gene activity and neuroinflammation was substantially reduced.
The researchers saw a similar phenomenon in mouse models for two other LSDs – palmitoyl-protein thioesterase 1 deficiency and lysosomal chloride channel deficiency. These and other LSD mouse models in the study were provided by Steven Gray, Ph.D., UTSW Professor of Pediatrics, in the Eugene McDermott Center for Human Growth and Development, of Molecular Biology, and of Neurology, who is an expert on gene therapy for LSD patients.
These results suggested STING drives neuroinflammation when lysosomes become damaged, a finding the researchers corroborated when they dosed healthy cells with a chemical that damages lysosomes. A closer look at gene expression in cells derived from the animal models showed that STING also increased the activity of genes associated with lysosome repair and new lysosome generation. Additional experiments in collaboration with Lu Sun, Ph.D., Assistant Professor of Molecular Biology and an expert on glial cells, showed this phenomenon depends on a protein called transcription factor EB (TFEB), which acts as a master controller of several lysosome-related genes.
Because the STING protein has multiple functional regions spanning the cell membrane, the researchers did additional experiments to determine which region might be responsible for lysosome generation. They found that the region located squarely within the cell membrane was key for this function. This “transmembrane” region is known to house a channel that helps membranous vesicles, such as lysosomes, regulate pH – a measure of acidity or alkalinity – by transporting pH-lowering protons across the membrane. Opening this channel on acidic vesicles releases protons, increasing the pH inside the vesicles and activating TFEB.
Dr. Yan and his colleagues hypothesize that because lysosomes normally degrade STING continuously, since it’s perpetually generated in cells, STING accumulation signals cells to kickstart the lysosome repair and generation pathway. In LSDs, this accumulation also prompts STING to generate inflammation. Thus, finding a way to dampen STING’s inflammatory role while encouraging its lysosome repair and generation role could offer a new way to treat LSDs, Dr. Yan said. Because lysosome dysfunction is also a prominent feature of other neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS), this strategy eventually could be used to treat these conditions as well.
Dr. Yan holds the Edwin L. Cox Distinguished Chair in Immunology and Genetics and is a Rita C. and William P. Clements, Jr. Scholar in Medical Research. Dr. Sun is a Southwestern Medical Foundation Scholar in Biomedical Research. Both are Investigators in the Peter O’Donnell Jr. Brain Institute and members of the Harold C. Simmons Comprehensive Cancer Center.
Other UTSW researchers who contributed to this study include first author Zhen Tang, B.S., Cong Xing, B.S., Antonina Araszkiewicz, M.S., and Devon Jeltema, B.S., all Immunology graduate students; Kun Yang, M.D., Ph.D., Instructor of Immunology; Wanwan Huai, Ph.D., postdoctoral fellow; Nicole Dobbs, Ph.D., Senior Scientist and Manager of the Yan Lab; and Yihe Zhang, B.S., Genetics, Development, and Disease graduate student.
This study was funded by grants from the National Institutes of Health (AI151708, AI185226, and NS122825) and UT Southwestern Endowed Scholar funds.
About UT Southwestern Medical Center
UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.