Researchers have discovered that the protein STING, previously known for its role in antiviral signaling, also plays a crucial part in cellular stress clearance and cell survival. This surprising finding suggests that the balance of STING’s two functions is essential for maintaining cellular health and could have significant implications for developing future therapies targeting age-related diseases.
STING’s Dual Roles
DNA is neatly packaged inside the nucleus and mitochondria of healthy human cells. DNA, though, is considered a ‘danger signal’ when it is present in the fluid component of the cell (the cytosol), and has been linked to infections, cellular stress external icon, cancerexternal icon, and other diseases.
Cells are also equipped with a sort of built-in alarm that is triggered when they detect this cytosolic DNA: the STING protein. When these bacteria and viruses come in, STING ramps up the inflammation needed to fend off these threats. Although transient activation of the STING-dependent inflammatory response is essential, a subset of people exhibit an abnormally activated STING pathway in which chronic expression has been associated with neurodegenerative diseases, other age-related pathologies and natural ageing.
Reveal STING Guard Duty
In trying to decipher the potential advantages of STING stimulation due central to different stressors, Dr. Jay Xiaojun Tan and colleagues performed a global protein level investigation in whole cells. These two factors, TFEB and TFE3, are pushed into the nucleus of cells to crank up production of lysosomes genes in response to STING activation.
Lysosomes are a type of organelle inside the cell that consist of an inner, acidic environment containing enzymes capable of breaking down many molecules and particles, including substances that have become ‘old’ or damaged. Cells also made more lysosomes, and upped autophagy in response to STING activation, by using TFEB and TFE3.
Lysosomes and autophagy are strongly linked to lifespan and healthspan (the length of time a person is healthy) so this protective effect of STING may be critical for something as fundamental to our biology as healthy aging. The study is a reminder that our understanding of the role of this intracellular innate immune regulator in inflammation and age-related diseases is far from complete, it questions the ongoing inhibitors on STING molecule to treat age-related diseases due their potential suppression on mitochondria biogenesis (which can potentiate defective autophagy/mitophagy) as well.
Conclusion
This finding also elucidates novel function of STING in facilitating autophagy-lysosome to preserve cellular quality and resist stress, which might represent a fundamental and phylogenetically conserved mechanism for cell vigor. This implies that subjecting our cells to moderate stress could help benefit them much like how exercise benefits our body, and potentially strengthen its stress response systems thereby delaying aging diseases which in turn pave the path towards healthspan. The normal equilibrium between the inflammatory and regulatory functions of STING is important, and inhibiting some downstream components of the inflammation pathway might be a more effective way to target STING for therapeutic purposes in the future.
