The protein STING has served researchers as a well-studied detector of “intruders” such as pathogens that need elimination, but re,newed attention on the molecule caught Japanese scientists by surprise after finding this protein also helps clear away non-cellular debris and further gird against catastrophic aging-related side effects with no role in disease fighting. A greater understanding of this phenomenon could also have profound implications for the development of therapies in age-related diseases.
The Duality of STING
Scientists discovered that the well-known antiviral protein STING – (previously thought to act mainly in immune cells) has a major black box function for defending cell health. Scientists at the University of Pittsburgh in collaboration with UPMC Aging Institute have found that STING is not only a central coordinator of inflammation from potential threats arising from infection, cellular stress and cancer but also essential for clearing out stressful debris when cells are damaged.
Jay Xiaojun Tan, Ph.D., the study’s senior author. D., STING’s protective role in cell stress and damage, unexpected: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. These two functions of STING indicates that a proportional balance between strong inflammation or protection from cellular damage is fundamental in preserving healthy cells, and ultimately overall health.
STING activates autophagy
Upon STING activation, the researchers observed that TFEB and TFE3 transcription factors were translocated to the nucleus in order to account for their high presence of nuclei (Figure 5A); yet no NLS had been identified on those proteins. In the mouse embryonic stem cells, these transcription factors provoked greater numbers of lysosomes to be created, which are organelles that help with autophagy a process in cells that starts getting rid of damaged proteins and molecules to mend itself, working as a kind of cell cleaner or recycler.
An identified causal link between longevity and healthspan, the period of good health a person enjoys, is this upturn in lysosome production and autophagy triggered by STING. The researchers think that this role of STING in the protection from such stress responses is important to preserve cell function over time and hence maintain good quality control, a hallmark of healthy aging.
Intriguingly, this STING-induced autophagy-lysosome pathway is evolutionally more ancient than its inflammation function which evolved only in vertebrates. In doing so, it points to the possibility that clearance of cellular stress and survival are a basic function of STING.
Conclusion
Effects of STING Activation During Inflammation and in Remodeling CellsThe marked consequences of activation were unexpected, however the finding that STING performs two different cellular roles one during inflammation and another responsible for clearing waste from (supposedly remodeling) cells has profound implications on how to design therapies for age-related diseases. We are just at the beginning of exploring treatments that block STING, but given the potential benefits of STING-mediated autophagy (autophagic protein degradation) this may not be the best approach as it would also interrupt these beneficial functions. Rather, hitting elements of the inflammation pathway beyond STING might be a more viable target while still keeping the proteins protective functions.
The researchers also suggest that mild cellular stress that activates STING could be a way to keep lysosomes in shape along with autophagy, the process by which our bodies break down cells and prevent diseases such as cancer, which in many ways is like exercise challenging our system and ultimately improves health. An understanding of this delicate balance may shape new strategies that can delay age-related diseases and enhance healthspan.
