@article{99893ca3e3f54a62a82ef6750b839514,
title = "DNA-induced 2'3'-cGAMP enhances haplotype-specific human STING cleavage by dengue protease",
abstract = "The cytosolic DNA sensor cGMP-AMP synthase (cGAS) synthesizes the noncanonical cyclic dinucleotide 2'3'-cGAMP to activate the adaptor protein stimulator of IFN genes (STING), thus awakening host immunity in response to DNA pathogen infection. However, dengue virus (DENV), an RNA virus without a DNA stage in its life cycle, also manipulates cGAS-STING-mediated innate immunity by proteolytic degradation of STING. Here, we found that the sensitivity of STING to DENV protease varied with different human STING haplotypes. Exogenous DNA further enhanced DENV protease's ability to interact and cleave protease-sensitive STING. DNAenhanced STING cleavage was reduced in cGAS-knockdown cells and triggered by the cGAS product 2'3'-cGAMP. The source of DNA may not be endogenous mitochondrial DNA but rather exogenous reactivated viral DNA. Cells producing 2'3'-cGAMP by overexpressing cGAS or with DNA virus reactivation enhanced STING cleavage in neighboring cells harboring DENV protease. DENV infection reduced host innate immunity in cells with the protease-sensitive STING haplotype, whose homozygote genotype frequency was found significantly reduced in Taiwanese people with dengue fever. Therefore, the human STING genetic background and DNA pathogen coinfection may be the missing links contributing to DENV pathogenesis.",
author = "Su, {Chan I.} and Kao, {Yu Ting} and Chang, {Chao Chen} and Yao Chang and Ho, {Tzong Shiann} and Sun, {H. Sunny} and Lin, {Yi Ling} and Lai, {Michael M.C.} and Liu, {Yu Huei} and Yu, {Chia Yi}",
note = "Funding Information: ACKNOWLEDGMENTS. We thank Chi-Ting Shie, Hsin-I Wang, and Zih-Shiuan Chuang for technical support. We also thank the technical support on mass spectrometry-based quantification of 2′3′-cGAMP from Dr. Der-Yen Lee (Graduate Institute of Integrated Medicine, China Medical University). This work was supported by the Ministry of Science and Technology (MOST), Taiwan, Grant 106-2320-B-400-031-MY3 and National Health Research Institutes, Taiwan, Grants IV-108-PP-27 and MR-108-GP-06 to C.-Y.Y. M.M.C.L. was funded by the Kwoh-Ting Li Foundation from the Development of Science and Technology, Taiwan. Y.-L.L. was supported by Academia Sinica and MOST Grant 108-2321-B-001-011. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding Information: We thank Chi-Ting Shie, Hsin-I Wang, and Zih-Shiuan Chuang for technical support. We also thank the technical support on mass spectrometry-based quantification of 2'3'-cGAMP from Dr. Der-Yen Lee (Graduate Institute of Integrated Medicine, China Medical University). This work was supported by the Ministry of Science and Technology (MOST), Taiwan, Grant 106-2320-B-400-031-MY3 and National Health Research Institutes, Taiwan, Grants IV-108-PP-27 and MR-108-GP-06 to C.-Y.Y. M.M.C.L. was funded by the Kwoh-Ting Li Foundation from the Development of Science and Technology, Taiwan. Y.-L.L. was supported by Academia Sinica and MOST Grant 108-2321-B-001-011. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2020 National Academy of Sciences. All rights reserved.",
year = "2020",
month = jul,
day = "7",
doi = "10.1073/pnas.1922243117",
language = "English",
volume = "117",
pages = "15947--15954",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "27",
}