STING protein plays a novel role in cellular stress clearance and survival

A protein called STING, previously shown to control a pathway that contributes to antiviral signaling, also plays an important role in clearing cellular stress and cell survival, according to a new study published in Molecular Cell.

It was very surprising that STING has a protective function for cells to reduce stress and damage in addition to its known role in inflammation.”

Jay Xiaojun Tan, Ph.D., senior author, assistant professor at the University of Pittsburgh and UPMC Institute on Aging and Pitt’s Department of Cell Biology

“Our findings suggest that the balance of STING’s two functions is important for cell health and could have implications for the future development of therapeutics for age-related diseases,” added first author Dr. Bo Lv, Ph.D., postdoctoral researcher in Tan’s lab.

In healthy human cells, DNA is packaged within the nucleus and mitochondria. When DNA leaks into the fluid component of the cell known as the cytosol, it means something is wrong.

“Cytoplasmic DNA is a danger signal associated with infections, cellular stress, cancer and other diseases,” Tan explained. “Cells have a warning system to detect DNA in the cytoplasm, which involves the activation of STING, which in turn orchestrates the inflammation necessary to combat these threats.”

While short bursts of STING-induced inflammation are crucial, in some people this pathway is chronically “active,” a condition that has been linked to neurodegeneration and other diseases of aging, as well as normal aging.

To learn more about the potential benefits of STING activation in response to different stresses, Tan and his team analyzed the full set of proteins inside the cells. They found that when STING was activated, two transcription factors called TFEB and TFE3 moved into the nucleus of cells, where they activated genes that resulted in the production of more lysosomes.

“Lysosomes are organelles involved in autophagy, a cellular process that cleans up damaged material, almost like a housekeeping or recycling system,” Tan said. “In response to STING activation, cells used TFEB and TFE3 to produce more lysosomes and increase autophagy.”

Both lysosomes and autophagy are closely related to longevity and health duration, the length of time a person is healthy, suggesting that this protective function of STING is important for healthy aging.

STING-blocking therapies are currently being investigated in the context of age-related diseases, but according to Tan, the new findings suggest that this strategy should be reconsidered because it would also block its autophagy/lysosome-promoting functions STING. Instead, selectively targeting components of the inflammatory pathway downstream of STING may be a better approach because it would preserve the beneficial functions of the protein.

Notably, TFEB and TFE3 are present throughout the animal kingdom, indicating that the STING-induced autophagy-lysosome pathway is more ancient evolutionarily than its inflammasome function, which is found only in vertebrates.

The newly discovered function of STING may be an ancient way cells maintain quality control, clear abnormal materials and manage cellular stress.

Tan hypothesizes that the mild cellular stress that activates STING may be important for maintaining the quality of lysosomes and autophagy responses, just as exercise improves our health by challenging our bodies.

“When we exercise regularly, we cause physical damage to our muscles, which activates repair systems that over-repair and ultimately build muscle,” he said. “I want to understand whether challenging our cells with mild stress in general could enhance stress response systems, including lysosome activity, and help delay age-related diseases and improve health span” .

Other authors on the study were William Dion, Haoxiang Yang, Jinrui Xun, MD, Bokai Zhu, Ph.D., all of Pitt. and Do-Hyung Kim, Ph.D., of the University of Minnesota.

This work was supported in part by the National Institutes of Health (NIH) National Institute of General Medical Sciences (R35GM150506 and R35GM130353) and the NIH National Institute on Aging (K01AG075142).