Cells constantly face stress from infection, diseases, and aging. To detect foreign DNA threats, they use the cGAS-STING pathway, a defense mechanism that is conserved across species. The STING protein is crucial for antiviral and inflammatory responses through type I interferon production, a function recently identified in vertebrates.1 However, cells can also alleviate cellular stress and promote survival by removing harmful material. This led Jay Xiaojun Tan, a cellular biologist from the University of Pittsburgh, to explore whether the cGAS-STING pathway had other overlooked roles in stress management.

“We thought [this pathway] should have protective functions or stress clearance functions, in addition to the very famous inflammation function.” Tan’s team explored whether the cGAS-STING pathway interacts with lysosomes, the cell’s housekeeping organelle responsible for clearing cellular damage and promoting longevity. Their findings, published in Molecular Cell, revealed an ancient role for this pathway in lysosomal biogenesis and stress clearance, which predates type I interferons.2
When STING is triggered, TANK-binding kinase (TBK1) activates and leads to interferon production. However, Tan and his team wanted to identify other transcription factors regulated by STING. On screening human cells to identify proteins that shuttled from the cytosol to the nucleus during STING activation, they identified 17 candidates.
Among these, the transcription factors EB (TFEB) and E3 (TFE3) caught Tan’s attention, because their activation coincided with genes that increased lysosome production. TFEB is also an ancient regulator of autophagy and innate immunity.3
Through cell-based assays, the researchers determined that STING activated TBK1 and TFEB independently, where the lipidation of autophagy proteins mediated TFEB activation. Using RNA sequencing, they identified upregulated genes during this process. They noted an increase in TFEB-target genes that promote lysosomal biogenesis and autophagy, supporting a cytoprotective rather than an inflammatory role.
Tan hopes these insights will support therapeutic development, as chronic activation of STING is seen in aging and neurodegenerative diseases like Alzheimer’s disease, which involve impaired lysosome trafficking.
Nan Yan, a molecular biologist at the University of Texas Southwestern Medical Center, who was not involved in the study, remarked, “This paper shows the good and bad activity coming from different parts of the protein. So conceivably, you can selectively manipulate either one.”
- Margolis SR, et al. Trends Immunol. 2017;38(10):733-743.
- Lv B, et al. Mol Cell. 2024;84(20):3979-3996.e9
- Visvikis O, et al. Immunity. 2014;40(6):896-909.