Wei Wan's team discovers lysosome biogenesis as a novel function of the cGAS-STING pathway
Source：Wei Wan
2025-02-17
The innate immune system serves as the first line of defense against pathogen infection. It employs diverse pattern recognition receptors (PRRs) distributed inside and outside cells to detect pathogen components and activate immune responses. When pathogen-derived DNA fragments leak into the cytoplasm of host cells, they are recognized and bound by the enzyme cGAS. DNA-bound cGAS is then activated and produces the second messenger cGAMP, which binds and activates the endoplasmic reticulum-resident protein STING. This triggers STING’s intracellular trafficking, ultimately promoting the production of type I interferons (IFNs) and inflammatory cytokines. Recent studies have shown that the cGAS-STING pathway can promote pathogen clearance by activating autophagy, a lysosome-dependent degradation process. However, whether this pathway regulates lysosomal function remains unclear.
On February 11, 2025, a team led by Wei Wan from Zhejiang University School of Medicine published a groundbreaking study titled “The cGAS-STING pathway activates transcription factor TFEB to stimulate lysosome biogenesis and pathogen clearance” in Immunity. The study revealed lysosome biogenesis as a novel function of the cGAS-STING pathway. The team demonstrated that activation of the cGAS-STING pathway significantly increases the number and activity of lysosomes, independent of type I IFNs or inflammatory cytokines. Mechanistically, the cGAS-STING pathway activates the transcription factor TFEB, driving the expression of lysosome-related genes and promoting lysosome biogenesis. Functionally, STING-induced TFEB activation and lysosome biogenesis not only enhance pathogen clearance, but also prevent excessive and prolonged activation of the cGAS-STING pathway by promoting the degradation of cytoplasmic DNA.
Wei Wan’s team has long been focused on the regulatory mechanisms and physiological functions of the autophagy-lysosome system. Their prior work uncovered several mechanisms underlying the cGAS-STING pathway-induced autophagosome formation. For instance, they found that STING directly recruits the autophagy-related protein WIPI2 to STING vesicles to facilitate autophagosome membrane elongation. Additionally, they revealed that the cGAS-STING pathway promotes ATG7 deacetylation to enhance its enzymatic activity, thereby initiating autophagy. While these studies focus on autophagosome formation, the latest research highlights that the cGAS-STING pathway also boosts lysosome biogenesis. It seems that lysosome function and autophagy process are coordinately regulated by the cGAS-STING pathway to facilitate the autophagic degradation.
In the same issue of Immunity, Wen Zhou from Southern University of Science and Technology published a commentary, emphasizing that Wei Wan’s team discovered a previously unrecognized function of the cGAS-STING pathway. Wen Zhou noted that this function represents a potent cell-autonomous immune response against the invading pathogens, pre-dating the emergence of type I IFN response. The team was also invited to publish a commentary in Autophagy to summarize and discuss their findings.
Wei Wan and Wei Liu from Zhejiang University School of Medicine are the corresponding authors. Yinfeng Xu from Hunan First Normal University is the first author and co-corresponding author. Other co-authors include Qian Wang, Chuying Qian, Yusha Wang, Jun Wang, Sheng Lu, Lijiang Song, and Zhengfu He from Zhejiang University School of Medicine.
Article Link: https://www.cell.com/immunity/fulltext/S1074-7613(24)00532-6
On February 11, 2025, a team led by Wei Wan from Zhejiang University School of Medicine published a groundbreaking study titled “The cGAS-STING pathway activates transcription factor TFEB to stimulate lysosome biogenesis and pathogen clearance” in Immunity. The study revealed lysosome biogenesis as a novel function of the cGAS-STING pathway. The team demonstrated that activation of the cGAS-STING pathway significantly increases the number and activity of lysosomes, independent of type I IFNs or inflammatory cytokines. Mechanistically, the cGAS-STING pathway activates the transcription factor TFEB, driving the expression of lysosome-related genes and promoting lysosome biogenesis. Functionally, STING-induced TFEB activation and lysosome biogenesis not only enhance pathogen clearance, but also prevent excessive and prolonged activation of the cGAS-STING pathway by promoting the degradation of cytoplasmic DNA.
Wei Wan’s team has long been focused on the regulatory mechanisms and physiological functions of the autophagy-lysosome system. Their prior work uncovered several mechanisms underlying the cGAS-STING pathway-induced autophagosome formation. For instance, they found that STING directly recruits the autophagy-related protein WIPI2 to STING vesicles to facilitate autophagosome membrane elongation. Additionally, they revealed that the cGAS-STING pathway promotes ATG7 deacetylation to enhance its enzymatic activity, thereby initiating autophagy. While these studies focus on autophagosome formation, the latest research highlights that the cGAS-STING pathway also boosts lysosome biogenesis. It seems that lysosome function and autophagy process are coordinately regulated by the cGAS-STING pathway to facilitate the autophagic degradation.
In the same issue of Immunity, Wen Zhou from Southern University of Science and Technology published a commentary, emphasizing that Wei Wan’s team discovered a previously unrecognized function of the cGAS-STING pathway. Wen Zhou noted that this function represents a potent cell-autonomous immune response against the invading pathogens, pre-dating the emergence of type I IFN response. The team was also invited to publish a commentary in Autophagy to summarize and discuss their findings.
Wei Wan and Wei Liu from Zhejiang University School of Medicine are the corresponding authors. Yinfeng Xu from Hunan First Normal University is the first author and co-corresponding author. Other co-authors include Qian Wang, Chuying Qian, Yusha Wang, Jun Wang, Sheng Lu, Lijiang Song, and Zhengfu He from Zhejiang University School of Medicine.
Article Link: https://www.cell.com/immunity/fulltext/S1074-7613(24)00532-6
