STING operation in protecting cells against stress | Summary of TS

Cells are constantly exposed to stress related to infections, diseases and aging. To detect foreign DNA threats, they use cGAS-STING pathwaya defense mechanism preserved across species. The STING protein is crucial for antiviral and inflammatory responses through the production of type I interferon recently identified in vertebrates.¹ However, cells can also relieve cellular stress and promote survival by removing harmful material. This led Jay Xiaojun Tancell biologist at the University of Pittsburgh to investigate whether the cGAS-STING pathway plays other overlooked roles in stress management.

“We thought (this pathway) should have a protective or stress-removing function, in addition to its very well-known inflammatory function.” Tan’s team investigated whether the cGAS-STING pathway interacts with lysosomes, a cell cleaning organelle responsible for repairing cellular damage and promoting longevity. Their arrangementspublished in molecular cell, revealed an ancient role for this pathway in lysosome biogenesis and stress resolution that predates type I interferons.²

When STING is triggered, TANK-binding kinase (TBK1) is activated, leading to the production of interferon. However, Tan and his team wanted to identify other transcription factors regulated by STING. Screening human cells to identify proteins that translocate from the cytosol to the nucleus during STING activation identified 17 candidates.

Among them, transcription factors EB (TFEB) and E3 (TFE3) caught Tan’s attention because their activation coincided with genes that increase lysosome production. TFEB is also ancient regulator autophagy and innate immunity.³

Scientists determined this using cell tests STING independently activated TBK1 and TFEB, where lipidation of autophagy proteins mediated TFEB activation. Using RNA sequencing, they identified genes whose expression was increased in this process. They noted an increase in TFEB target genes that promote lysosomal biogenesis and autophagy, supporting a cytoprotective rather than inflammatory role.

Tan hopes these findings will support therapeutic development, as chronic STING activation is observed in aging and neurodegenerative diseases such as Alzheimer’s disease, which involve impaired lysosomal transport.

NanYana molecular biologist at the University of Texas Southwestern Medical Center who was not involved in the study noted: “This paper shows the good and bad activity of different parts of the protein. So it’s possible that you can selectively manipulate any of them.