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The STING ligand 2’3’-cGAMP induces an NF-κB-dependent anti-bacterial innate immune response in the starlet sea anemone Nematostella vectensis

View ORCID ProfileShally R. Margolis, View ORCID ProfilePeter A. Dietzen, View ORCID ProfileBeth M. Hayes, Stephen C. Wilson, View ORCID ProfileBrenna C. Remick, View ORCID ProfileSeemay Chou, View ORCID ProfileRussell E. Vance
doi: https://doi.org/10.1101/2021.05.13.443009
Shally R. Margolis
1Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720 USA
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Peter A. Dietzen
1Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720 USA
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Beth M. Hayes
2Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA
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Stephen C. Wilson
1Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720 USA
3Bristol Myers Squibb, 200 Cambridgepark Dr., Cambridge, MA 02140
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Brenna C. Remick
1Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720 USA
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Seemay Chou
2Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA
4Chan Zuckerberg Biohub, San Francisco, CA
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Russell E. Vance
1Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720 USA
5Cancer Research Laboratory and the Immunotherapeutics and Vaccine Research Initiative, University of California, Berkeley, CA 94720
6Howard Hughes Medical Institute, University of California, Berkeley, CA 94720
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  • For correspondence: rvance@berkeley.edu
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Abstract

In mammals, the cGAS-cGAMP-STING pathway is crucial for sensing viral infection and initiating an anti-viral type I interferon response. cGAS and STING are highly conserved genes that originated in bacteria and are present in most animals. By contrast, interferons only emerged in vertebrates; thus, the function of STING in invertebrates is unclear. Here, we use the STING ligand 2’3’-cGAMP to activate immune responses in a model cnidarian invertebrate, the starlet sea anemone Nematostella vectensis. Using RNA-Seq, we found that 2’3’-cGAMP induces robust transcription of both anti-viral and anti-bacterial genes, including the conserved transcription factor NF-κB. Knockdown experiments identified a role for NF-κB in specifically inducing anti-bacterial genes downstream of 2’3’-cGAMP, and some of these genes were also found to be induced during Pseudomonas aeruginosa infection. Furthermore, we characterized the protein product of one of the putative anti-bacterial genes, the N. vectensis homolog of Dae4, and found that it has conserved anti-bacterial activity. This work describes an unexpected role of a cGAMP sensing pathway in anti-bacterial immunity and suggests that a broad transcriptional response is an evolutionarily ancestral output of 2’3’-cGAMP signaling in animals.

Significance statement Anti-viral immune responses are initiated via signaling pathways such as the STING pathway. In mammals, activation of this pathway results in the production of anti-viral molecules called interferons. Surprisingly, the STING pathway is present in organisms such as sea anemones that lack interferons; the function of this pathway in these organisms is thus unclear. Here we report that in the anemone Nematostella vectensis, a small molecule activator of the STING pathway, cGAMP, not only induces an anti-viral response, but also stimulates an anti-bacterial immune response. These results provide insights into the evolutionary origins of innate immunity, and suggest a broader ancestral role for cGAMP-STING signaling that evolved toward more specialized anti-viral functions in mammals.

Competing Interest Statement

R.E.V. consults for Ventus Therapeutics. The other authors declare no competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted May 14, 2021.
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The STING ligand 2’3’-cGAMP induces an NF-κB-dependent anti-bacterial innate immune response in the starlet sea anemone Nematostella vectensis
Shally R. Margolis, Peter A. Dietzen, Beth M. Hayes, Stephen C. Wilson, Brenna C. Remick, Seemay Chou, Russell E. Vance
bioRxiv 2021.05.13.443009; doi: https://doi.org/10.1101/2021.05.13.443009
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The STING ligand 2’3’-cGAMP induces an NF-κB-dependent anti-bacterial innate immune response in the starlet sea anemone Nematostella vectensis
Shally R. Margolis, Peter A. Dietzen, Beth M. Hayes, Stephen C. Wilson, Brenna C. Remick, Seemay Chou, Russell E. Vance
bioRxiv 2021.05.13.443009; doi: https://doi.org/10.1101/2021.05.13.443009

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