Selective Loss of Responsiveness to Exogenous but Not Endogenous Cyclic-Dinucleotides in Mice Expressing STING-R231H
Stimulator of interferon genes (STING) plays a central role in innate immune responses to viral and intracellular bacterial infections, and cellular damage. STING is a cytosolic sensor of cyclic dinucleotides (CDNs) including those produced by pathogenic bacteria and those arising endogenously as pr...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.00238/full |
| _version_ | 1818510973992960000 |
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| author | Melissa M. Walker Soojin Kim William J. Crisler Kimberlie Nguyen Laurel L. Lenz Laurel L. Lenz John C. Cambier John C. Cambier Andrew Getahun Andrew Getahun |
| author_facet | Melissa M. Walker Soojin Kim William J. Crisler Kimberlie Nguyen Laurel L. Lenz Laurel L. Lenz John C. Cambier John C. Cambier Andrew Getahun Andrew Getahun |
| author_sort | Melissa M. Walker |
| collection | DOAJ |
| description | Stimulator of interferon genes (STING) plays a central role in innate immune responses to viral and intracellular bacterial infections, and cellular damage. STING is a cytosolic sensor of cyclic dinucleotides (CDNs) including those produced by pathogenic bacteria and those arising endogenously as products of the DNA sensor cGAS (e.g., 2′3′ cGAMP). The two most common alternative allelic variants of STING in humans are STING-R71H-G230A-R293Q (STING-HAQ) and STING-R232H that are found in 20.4% and 13.7–17.6% of the population, respectively. To determine the biologic consequences of these genotypic variations, we generated knock-in mice containing the murine equivalents of each variant and studied their responsiveness to CDNs. Homozygous STING-HAQ (R71H-I229A-R292Q) and STING-R231H mice were found to be unresponsive to all exogenous CDNs tested (ci-di-GMP, ci-di-AMP, 3′3′ cGAMP and Rp,Rp-CDA). Responses of homozygous STING-HAQ mice to endogenous 2′3′ cGAMP was also greatly impaired. However, homozygous STING-R231H mice are fully responsive to 2′3′ cGAMP. Analysis of heterozygous mice revealed reduced responsiveness to exogenous and endogenous CDNs in mice carrying a single copy of STING-HAQ, while STING-R231H heterozygous mice exhibit reduced responsiveness to exogenous but not endogenous CDNs. These findings confirm and extend previous reports by demonstrating differing impact of allelic variation of STING on the ability to sense and respond to exogenous vs. endogenous CDNs. Finally, the STING-R231H variant mouse represents a useful tool with which to examine the relative contributions of STING sensing of exogenous and endogenous CDNs in the context of bacterial infections and CDN-based cancer immunotherapeutics. |
| first_indexed | 2024-12-10T23:27:16Z |
| format | Article |
| id | doaj.art-9c135511f7434450b8fd32851c4ee559 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-10T23:27:16Z |
| publishDate | 2020-02-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-9c135511f7434450b8fd32851c4ee5592022-12-22T01:29:32ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-02-011110.3389/fimmu.2020.00238508053Selective Loss of Responsiveness to Exogenous but Not Endogenous Cyclic-Dinucleotides in Mice Expressing STING-R231HMelissa M. Walker0Soojin Kim1William J. Crisler2Kimberlie Nguyen3Laurel L. Lenz4Laurel L. Lenz5John C. Cambier6John C. Cambier7Andrew Getahun8Andrew Getahun9Department of Immunology and Microbiology, University of Colorado SOM, Aurora, CO, United StatesDepartment of Immunology and Microbiology, University of Colorado SOM, Aurora, CO, United StatesDepartment of Immunology and Microbiology, University of Colorado SOM, Aurora, CO, United StatesDepartment of Immunology and Microbiology, University of Colorado SOM, Aurora, CO, United StatesDepartment of Immunology and Microbiology, University of Colorado SOM, Aurora, CO, United StatesDepartment of Biomedical Sciences, National Jewish Health, Denver, CO, United StatesDepartment of Immunology and Microbiology, University of Colorado SOM, Aurora, CO, United StatesDepartment of Biomedical Sciences, National Jewish Health, Denver, CO, United StatesDepartment of Immunology and Microbiology, University of Colorado SOM, Aurora, CO, United StatesDepartment of Biomedical Sciences, National Jewish Health, Denver, CO, United StatesStimulator of interferon genes (STING) plays a central role in innate immune responses to viral and intracellular bacterial infections, and cellular damage. STING is a cytosolic sensor of cyclic dinucleotides (CDNs) including those produced by pathogenic bacteria and those arising endogenously as products of the DNA sensor cGAS (e.g., 2′3′ cGAMP). The two most common alternative allelic variants of STING in humans are STING-R71H-G230A-R293Q (STING-HAQ) and STING-R232H that are found in 20.4% and 13.7–17.6% of the population, respectively. To determine the biologic consequences of these genotypic variations, we generated knock-in mice containing the murine equivalents of each variant and studied their responsiveness to CDNs. Homozygous STING-HAQ (R71H-I229A-R292Q) and STING-R231H mice were found to be unresponsive to all exogenous CDNs tested (ci-di-GMP, ci-di-AMP, 3′3′ cGAMP and Rp,Rp-CDA). Responses of homozygous STING-HAQ mice to endogenous 2′3′ cGAMP was also greatly impaired. However, homozygous STING-R231H mice are fully responsive to 2′3′ cGAMP. Analysis of heterozygous mice revealed reduced responsiveness to exogenous and endogenous CDNs in mice carrying a single copy of STING-HAQ, while STING-R231H heterozygous mice exhibit reduced responsiveness to exogenous but not endogenous CDNs. These findings confirm and extend previous reports by demonstrating differing impact of allelic variation of STING on the ability to sense and respond to exogenous vs. endogenous CDNs. Finally, the STING-R231H variant mouse represents a useful tool with which to examine the relative contributions of STING sensing of exogenous and endogenous CDNs in the context of bacterial infections and CDN-based cancer immunotherapeutics.https://www.frontiersin.org/article/10.3389/fimmu.2020.00238/fullSTINGcGAScyclic dinucleotideallelic variantsinfectioncancer |
| spellingShingle | Melissa M. Walker Soojin Kim William J. Crisler Kimberlie Nguyen Laurel L. Lenz Laurel L. Lenz John C. Cambier John C. Cambier Andrew Getahun Andrew Getahun Selective Loss of Responsiveness to Exogenous but Not Endogenous Cyclic-Dinucleotides in Mice Expressing STING-R231H Frontiers in Immunology STING cGAS cyclic dinucleotide allelic variants infection cancer |
| title | Selective Loss of Responsiveness to Exogenous but Not Endogenous Cyclic-Dinucleotides in Mice Expressing STING-R231H |
| title_full | Selective Loss of Responsiveness to Exogenous but Not Endogenous Cyclic-Dinucleotides in Mice Expressing STING-R231H |
| title_fullStr | Selective Loss of Responsiveness to Exogenous but Not Endogenous Cyclic-Dinucleotides in Mice Expressing STING-R231H |
| title_full_unstemmed | Selective Loss of Responsiveness to Exogenous but Not Endogenous Cyclic-Dinucleotides in Mice Expressing STING-R231H |
| title_short | Selective Loss of Responsiveness to Exogenous but Not Endogenous Cyclic-Dinucleotides in Mice Expressing STING-R231H |
| title_sort | selective loss of responsiveness to exogenous but not endogenous cyclic dinucleotides in mice expressing sting r231h |
| topic | STING cGAS cyclic dinucleotide allelic variants infection cancer |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.00238/full |
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