Inflammatory Trigger STING is Found to Also Regulate Aspects of Lysosomal Function
One of the reasons why older people exhibit chronic inflammation is that innate immune pathways such as that involving the STING protein react inappropriately to signs of age-related molecular damage in the cell, such as mislocalized mitochondrial DNA. Thus some research has aimed at producing ways to inhibit STING activity. A big issue with all such suppression of inflammatory regulators is that the normal, necessary inflammation required for defense against pathogens and coordination of regeneration makes use of the same pathways. No-one has yet found a way to suppress only unwanted inflammation by targeting regulators of inflammation. The only way forward appears to be to remove the triggers of inflammation, a task that remains a sizable challenge for most of those triggers.
Here, researchers find another blocking issue specific to STING, which is that in addition to promoting inflammation the protein also acts to improve autophagy via increased creation of lysosomes. Autophagy is a complex cell maintenance process that delivers surplus and damaged proteins and structures to a lysosome for disassembly into raw materials for further protein synthesis. It is well demonstrated that improved autophagy modestly slows aging, even if specifically achieved by only improving lysosomal function. Suppressing STING would therefore impair autophagy and modestly accelerate aging, likely ruling this out as a strategy for reducing age-related chronic inflammation.
Double-edged STING: study identifies new pathway involved in aging
In healthy human cells, DNA is packaged up inside the nucleus and mitochondria. When DNA leaks out into the fluid component of the cell known as the cytosol, it means that something is wrong. 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. While short bursts of STING-mediated inflammation are crucial, in some people this pathway is chronically "on," a state that has been linked with neurodegeneration and other diseases of aging, as well as normal aging.
To learn more about potential benefits of STING activation in response to diverse stresses, researchers analyzed the full set of proteins within cells. They found that when STING was activated, two transcription factors called TFEB and TFE3 were shuttled to the nucleus of cells, where they activated genes that resulted in the production of more lysosomes. Lysosomes are organelles that are involved in autophagy, a cellular process that cleans up damaged material, almost like a housekeeping or recycling system. Both lysosomes and autophagy are tightly linked with longevity and healthspan, the length of time that a person is healthy, suggesting that this protective function of STING is important for healthy aging.
STING-blocking therapies are currently being explored within the context of age-related diseases, but the new 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 inflammation pathway downstream of STING may be a better approach because it would preserve the protein's beneficial functions.
A TBK1-independent primordial function of STING in lysosomal biogenesis
Stimulator of interferon genes (STING) is activated in many pathophysiological conditions, leading to TBK1-dependent interferon production in higher organisms. However, primordial functions of STING independent of TBK1 are poorly understood. Here, through proteomics and bioinformatics approaches, we identify lysosomal biogenesis as an unexpected function of STING.
Transcription factor EB (TFEB), an evolutionarily conserved regulator of lysosomal biogenesis and host defense, is activated by STING from multiple species, including humans, mice, and frogs. STING-mediated TFEB activation is independent of TBK1, but it requires STING trafficking and its conserved proton channel. GABARAP lipidation, stimulated by the channel of STING, is key for STING-dependent TFEB activation. STING stimulates global upregulation of TFEB-target genes, mediating lysosomal biogenesis and autophagy. TFEB supports cell survival during chronic sterile STING activation, a common condition in aging and age-related diseases. These results reveal a primordial function of STING in the biogenesis of lysosomes, essential organelles in immunity and cellular stress resistance.