A Novel Function for STING in DNA Damage Response

A study published in the journal Molecular Cell has shed light on the multifaceted role of STING, a protein previously implicated in antiviral signaling pathways. The study reveals that STING also plays a crucial part in facilitating cellular stress resolution and promoting cell survival.

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

Dr. Jay Xiaojun Tan, Assistant Professor and Study Senior Author, Department of Cell Biology, University of Pittsburgh

“Our findings suggest that the balance of STING’s two functions is important for the health of cells and could have implications for future development of therapeutics for age-related diseases,” added Study First Author Dr. Bo Lv, a Postdoctoral Researcher in Tan’s lab.

In normal cellular environments, DNA is tightly compartmentalized within the nucleus and mitochondria. However, when DNA is released into the cytosol, a condition that deviates from the norm, it indicates an underlying cellular anomaly.

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

Dr. Jay Xiaojun Tan, Assistant Professor and Study Senior Author, Department of Cell Biology, University of Pittsburgh

Prolonged activation of the STING-mediated inflammatory response, which is typically reserved for short-lived bursts, has been implicated in the development of neurodegenerative disorders and other age-related conditions, as well as contributing to the normal aging process itself.

In a comprehensive study, Tan and his team delved into the proteome of cells to elucidate the effects of STING activation under various stress conditions. Their findings revealed that upon STING activation, the transcription factors TFEB and TFE3 were translocated to the nucleus, where they initiated the transcription of genes responsible for the enhanced biogenesis of lysosomes.

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

Dr. Jay Xiaojun Tan, Assistant Professor and Study Senior Author, Department of Cell Biology, University of Pittsburgh

Lysosomes and autophagy are closely connected to longevity and healthspan—the period during which a person remains healthy—implying that STING's protective role is crucial for promoting healthy aging.

Recent research indicates that targeting STING with STING-blocking therapies may not be the most effective strategy for addressing age-related diseases, as it could inadvertently compromise the protein's role in promoting autophagy and lysosome function.

A more promising approach may be to selectively target downstream components of the inflammation pathway, thereby preserving STING's beneficial functions while still mitigating its detrimental effects.

TFEB and TFE3 are found throughout the animal kingdom, suggesting that the STING-induced autophagy-lysosome pathway is evolutionarily older than its role in inflammation, which is exclusive to vertebrates.

The newly discovered role of STING may represent an ancient mechanism by which cells maintain quality control, remove abnormal materials, and manage cellular stress.

Tan suggests that mild cellular stress activating STING could be crucial for maintaining lysosome function and autophagy, similar to how exercise enhances health by challenging the body.

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