STING protein plays a up-to-date role in cellular stress relief and survival

A protein called STING, previously shown to control a pathway contributing to antiviral signaling, also plays an crucial role in resolving cellular stress and cell survival, according to a up-to-date paper published in Molecular cell.

“It was very surprising to find that, in addition to its well-known role in preventing inflammation, STING also has a protective function for cells, reducing stress and damage.”

Jay Xiaojun Tan, PhD, Senior Author, Assistant Professor, University of Pittsburgh and UPMC Institute on Aging, Department of Cell Biology, University of Pittsburgh

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

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

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

Although brief bursts of STING-mediated inflammation play a key role, in some people this pathway is chronically “turned on,” and this state has been implicated in neurodegeneration and other diseases of aging, as well as normal aging.

To learn more about the potential benefits of activating STING in response to different stresses, Tan and his team analyzed the entire set of proteins in cells. They found that when STING was activated, two transcription factors called TFEB and TFE3 were transported to the nucleus, where they turned on 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 cleaning or recycling system,” Tan says. “In response to STING activation, cells used TFEB and TFE3 to produce more lysosomes and escalate autophagy.”

Both lysosomes and autophagy are closely linked to longevity and robust lifespan, the period during which a person enjoys good health, suggesting that this protective function of STING is crucial for robust aging.

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

It is worth noting that TFEB and TFE3 are present throughout the animal kingdom, indicating that the autophagy and lysosomal pathway induced by STING is evolutionarily older than its inflammatory function, which is unique to vertebrates.

The newly discovered function of the STING protein may be an old way for cells to maintain quality control, remove abnormal substances and cope with cellular stress.

Tan hypothesizes that delicate cellular stress, which activates STING, may be crucial for maintaining the quality of lysosomes and the autophagy response, much like how exercise improves our health by challenging our bodies.

“When we exercise regularly, we cause physical damage to our muscles, which triggers repair systems that over-repair and ultimately build muscle,” he said. “I want to understand whether exposing our cells to delicate stress in general can strengthen stress response systems, including lysosomal activity, and assist delay age-related diseases and improve long-term health.”

Additional study authors included William Dion, Haoxiang Yang, Jinrui Xun, MD, PhD, Bokai Zhu, MD, PhD (all of Pitt), and Do-Hyung Kim, MD, PhD of the University of Minnesota.

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