Nuclear cGAS governs transcription to control lipid metabolism, tumor growth, and therapy response.
18 affiliations
- 1Lineberger Comprehensive Cancer Center
- 2Department of Biochemistry and Biophysics
- 3Bioinformatics and Analytics Research Collaborative (BARC)
- 4Carolina Institute for Developmental Disabilities
- 5University of North Carolina (UNC) Neuroscience Center, and
- 6Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
- 7Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, North Carolina, USA.
- 8Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
- 9Department of Data Science, Dana-Farber Cancer Institute Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
- 10Marsico Lung Institute/UNC Cystic Fibrosis Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
- 11Department of Medicinal Chemistry, School of Pharmacy
- 12Philips Institute for Oral and Craniofacial Molecular Biology, School of Dentistry; and
- 13Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA.
- 14Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
- 15Department of Biology
- 16UNC Proteomics Core Facility, Department of Pharmacology
- 17Thurston Arthritis Research Center; and
- 18Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Abstract
Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor critical for host defense against microbial infections. To prevent aberrant activation, nuclear cGAS is restrained by nucleosome tethering or by barrier-to-autointegration factor-mediated restriction of its access to DNA. However, its physiological roles beyond enzymatic suppression in the nucleus remain poorly understood. Here, we present a genome-wide map of cGAS chromatin localization in human cells and unexpectedly find its binding beyond nucleosome tethering, where cGAS is recruited to chromatin by AP-1 transcription factors via a potentially previously uncharacterized transactivation domain. Integrated CUT&RUN, RNA-seq, and metabolomics analyses reveal that cGAS transcriptionally regulates cholesterol homeostasis. Mechanistically, cGAS promotes LGALS3 transcription, which inhibits ACAA2 activity to suppress fatty acid oxidation and acetyl-CoA production, thereby lowering intracellular cholesterol levels. Reduced cholesterol lowers plasma membrane phosphatidylinositol [3,4,5] triphosphate [PI(3,4,5)P3] levels and decreases mTOR complex 2 (mTORC2) activation. In contrast, cGAS depletion results in cholesterol accumulation and elevated PI(3,4,5)P3, driving mTORC2/Akt signaling, promoting xenografted tumor growth, and conferring resistance to DNA-damaging agents. In vivo, the elevated hepatic cholesterol levels observed in cGas-/- mice were largely reversed by inhibition of Akt but not STING, whereas cGAS deficiency had minimal effects on lung physiology. Collectively, our findings uncover an unexpected role for nuclear cGAS in orchestrating a transcriptional program that links lipid metabolism to cell proliferation, stress response, and cholesterol homeostasis in liver.
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BibTeX
@article{deng2026nuclear,
title = {{Nuclear cGAS governs transcription to control lipid metabolism, tumor growth, and therapy response.}},
author = {Yu Deng and Matthew J. Niederhuber and Zhichuan Zhu and Austin J. Hepperla and Le Yu and Quentin Hahn and Joshua Hartsell and Tooba Rashid and Piotr A. Mieczkowski and Hemant Kelkar and Jeremy M. Simon and Yanqiong Zhang and Alessandra Livraghi-Butrico and Meredith J. Zeller and Joseph G.C. Kennedy and Jazmin F. DePriest and Jiong Li and Yan Zhang and Xing Qiu and H. Ümit Kaniskan and Jian Jin and Corbin D. Jones and Laura E. Herring and Douglas H. Phanstiel and Xiaojing Liu and Jesse R. Raab and Brian D. Strahl and Pengda Liu},
journal = {The Journal of clinical investigation},
year = {2026},
month = nov,
doi = {10.1172/jci205579},
url = {https://europepmc.org/article/MED/42969224},
note = {CC BY},
}
RIS
TY - JOUR
TI - Nuclear cGAS governs transcription to control lipid metabolism, tumor growth, and therapy response.
AU - Yu Deng
AU - Matthew J. Niederhuber
AU - Zhichuan Zhu
AU - Austin J. Hepperla
AU - Le Yu
AU - Quentin Hahn
AU - Joshua Hartsell
AU - Tooba Rashid
AU - Piotr A. Mieczkowski
AU - Hemant Kelkar
AU - Jeremy M. Simon
AU - Yanqiong Zhang
AU - Alessandra Livraghi-Butrico
AU - Meredith J. Zeller
AU - Joseph G.C. Kennedy
AU - Jazmin F. DePriest
AU - Jiong Li
AU - Yan Zhang
AU - Xing Qiu
AU - H. Ümit Kaniskan
AU - Jian Jin
AU - Corbin D. Jones
AU - Laura E. Herring
AU - Douglas H. Phanstiel
AU - Xiaojing Liu
AU - Jesse R. Raab
AU - Brian D. Strahl
AU - Pengda Liu
PY - 2026
DA - 2026/11/02
JO - The Journal of clinical investigation
DO - 10.1172/jci205579
UR - https://europepmc.org/article/MED/42969224
AB - Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor critical for host defense against microbial infections. To prevent aberrant activation, nuclear cGAS is restrained by nucleosome tethering or by barrier-to-autointegration factor-mediated restriction of its access to DNA. However, its physiological roles beyond enzymatic suppression in the nucleus remain poorly understood. Here, we present a genome-wide map of cGAS chromatin localization in human cells and unexpectedly find its binding beyond nucleosome tethering, where cGAS is recruited to chromatin by AP-1 transcription factors via a potentially previously uncharacterized transactivation domain. Integrated CUT&RUN, RNA-seq, and metabolomics analyses reveal that cGAS transcriptionally regulates cholesterol homeostasis. Mechanistically, cGAS promotes LGALS3 transcription, which inhibits ACAA2 activity to suppress fatty acid oxidation and acetyl-CoA production, thereby lowering intracellular cholesterol levels. Reduced cholesterol lowers plasma membrane phosphatidylinositol [3,4,5] triphosphate [PI(3,4,5)P3] levels and decreases mTOR complex 2 (mTORC2) activation. In contrast, cGAS depletion results in cholesterol accumulation and elevated PI(3,4,5)P3, driving mTORC2/Akt signaling, promoting xenografted tumor growth, and conferring resistance to DNA-damaging agents. In vivo, the elevated hepatic cholesterol levels observed in cGas-/- mice were largely reversed by inhibition of Akt but not STING, whereas cGAS deficiency had minimal effects on lung physiology. Collectively, our findings uncover an unexpected role for nuclear cGAS in orchestrating a transcriptional program that links lipid metabolism to cell proliferation, stress response, and cholesterol homeostasis in liver.
SN - 0021-9738
SN - 1558-8238
ER -