A protein named STING, known for its role in regulating antiviral signaling pathways, has also been found to be crucial for clearing cellular stress and ensuring cell survival, according to a recent study published in Molecular Cell.
A protein named STING, which is recognized for managing a pathway related to antiviral signaling, also plays a vital role in the process of clearing cellular stress and promoting cell survival, as detailed in a fresh article in Molecular Cell.
“It surprised us to find that STING has a protective role in helping cells manage stress and damage, in addition to its established function in inflammation,” remarked senior author Jay Xiaojun Tan, Ph.D., an assistant professor at the University of Pittsburgh and UPMC Aging Institute, as well as at Pitt’s Department of Cell Biology.
“Our research indicates that the balance between STING’s two roles is crucial for cell health and could influence the future development of treatments for age-related illnesses,” added first author Dr. Bo Lv, Ph.D., a postdoc in Tan’s laboratory.
In healthy human cells, DNA is contained inside the nucleus and mitochondria. If DNA leaks into the cell’s cytosol, it signals that something is amiss.
“DNA in the cytosol acts as a danger signal linked to infections, cellular stress, cancer, and various other ailments,” Tan explained. “Cells have a detection system for cytosolic DNA, which activates STING and initiates inflammation to tackle these threats.”
While brief episodes of STING-driven inflammation are essential, some individuals experience a continuous activation of this pathway, which has been associated with neurodegeneration, other age-related diseases, and the aging process itself.
To explore the potential advantages of STING activation in response to various stressors, Tan and his team examined all proteins present in the cells. They discovered that when STING was activated, two transcription factors, TFEB and TFE3, were transported into the cell nucleus where they initiated the expression of genes that increased the production of lysosomes.
“Lysosomes are cellular organelles that play a key role in autophagy, a process that cleans up damaged components in cells, akin to a housekeeping or recycling system,” Tan noted. “Following STING activation, cells utilized TFEB and TFE3 to create more lysosomes, thereby boosting autophagy.”
Both lysosomes and autophagy are closely associated with longevity and healthy aging, implying that STING’s protective role is vital for promoting healthy aging.
Therapies aimed at blocking STING are currently being studied for age-associated diseases; however, Tan asserts that these new findings necessitate a reevaluation of this approach, as it could also interfere with STING’s beneficial roles in autophagy and lysosome production. A potentially more effective strategy may involve selectively targeting elements of the inflammatory pathway that are downstream of STING, which would help maintain the protein’s advantageous functions.
Importantly, TFEB and TFE3 can be found throughout the animal kingdom, suggesting that the autophagy-lysosome pathway activated by STING is evolutionarily older than its inflammatory role, which is found only in vertebrates.
The newly identified role of STING may represent a primal means by which cells maintain quality control, eliminate abnormal materials, and handle cellular stress.
Tan suggests that mild cellular stress, which activates STING, might be essential for sustaining lysosome integrity and enhancing autophagy responses, similar to how exercise benefits our health by putting physical strain on our bodies.
“When we engage in regular exercise, we inflict minor damage on our muscles, which triggers repair mechanisms that ultimately result in muscle growth,” he explained. “I aim to understand if exposing our cells to mild stress in general could strengthen stress response systems, including lysosome activity, thus aiding in the prevention of age-related diseases and enhancing healthspan.”
Other contributors to the study include William Dion, Haoxiang Yang, Jinrui Xun, M.D., Bokai Zhu, Ph.D., all from Pitt; and Do-Hyung Kim, Ph.D., from the University of Minnesota.
This research was partially funded by the National Institutes of Health (NIH), specifically the National Institute of General Medical Sciences (R35GM150506 and R35GM130353) and the NIH National Institute of Aging (K01AG075142).
