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Updated: Jul 4, 2025
Stimulation of Cytoplasmic DNA Sensing Pathways In Vitro and In Vivo
Published on: September 18, 2014
Micronucleus is not a potent inducer of the cGAS/STING pathway
Yuki Sato1,2, Makoto T Hayashi3,4
1Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
Abstract:
Micronuclei (MN) have been associated with the innate immune response. The abrupt rupture of MN membranes results in the accumulation of cGAS, potentially activating STING and downstream interferon-responsive genes. However, direct evidence connecting MN and cGAS activation has been lacking. We have developed the FuVis2 reporter system, which enables the visualization of the cell nucleus carrying a single sister chromatid fusion and, consequently, MN. Using this FuVis2 reporter equipped with cGAS and STING reporters, we rigorously assessed the potency of cGAS activation by MN in individual living cells. Our findings reveal that cGAS localization to membrane-ruptured MN during interphase is infrequent, with cGAS primarily capturing MN during mitosis and remaining bound to cytosolic chromatin. We found that cGAS accumulation during mitosis neither activates STING in the subsequent interphase nor triggers the interferon response. Gamma-ray irradiation activates STING independently of MN formation and cGAS localization to MN. These results suggest that cGAS accumulation in cytosolic MN is not a robust indicator of its activation and that MN are not the primary trigger of the cGAS/STING pathway.
Insights
Micronuclei (MN) do not robustly activate the cGAS-STING pathway. Researchers found cGAS rarely binds to ruptured MN, suggesting MN are not a primary trigger for this innate immune response.
Area of Science:
- Cell Biology
- Immunology
- Genetics
Background:
- Micronuclei (MN) are linked to innate immunity, with membrane rupture potentially releasing DNA to activate cGAS-STING.
- Previous studies lacked direct evidence linking MN to cGAS activation.
Purpose of the Study:
- To investigate the direct role of micronuclei in activating the cGAS-STING pathway using a novel reporter system.
- To visualize and quantify cGAS and STING activation in response to MN in living cells.
Main Methods:
- Development of the FuVis2 reporter system for visualizing sister chromatid fusions and MN.
- Simultaneous reporting of cGAS and STING activity in individual living cells.
- Assessment of cGAS localization and STING activation in response to MN formation and gamma-ray irradiation.
Main Results:
- cGAS primarily binds to MN during mitosis, not interphase, and remains associated with cytosolic chromatin.
- cGAS accumulation on mitotic MN does not lead to STING activation or interferon response in subsequent interphase.
- Gamma-ray irradiation activates STING independently of MN formation and cGAS localization.
Conclusions:
- cGAS accumulation on cytosolic MN is not a reliable indicator of cGAS activation.
- Micronuclei are unlikely to be the primary triggers of the cGAS-STING innate immune pathway.
