DNA-induced 2'3'-cGAMP enhances haplotype-specific human STING cleavage by dengue protease

Chan I. Su, Yu Ting Kao, Chao Chen Chang, Yao Chang, Tzong Shiann Ho, H. Sunny Sun, Yi Ling Lin, Michael M.C. Lai, Yu Huei Liu, Chia Yi Yu

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)15947-15954
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number27
DOIs
Publication statusPublished - 2020 Jul 7

All Science Journal Classification (ASJC) codes

  • General

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