Two cGAS-like receptors induce antiviral immunity in Drosophila

Holleufer, Andreas; Winther, Kasper Grønbjerg; Gad, Hans Henrik; Ai, Xianlong; Chen, Yuqiang; Li, Lihua; Wei, Ziquan; Deng, Huimin; Liu, Jiyong; Frederiksen, Ninna Ahlmann; Simonsen, Bine; Andersen, Line Lykke; Kleigrewe, Karin; Dalskov, Louise; Pichlmair, Andreas; Cai, Hua; Imler, Jean‐Luc; Hartmann, Rune

doi:10.1038/s41586-021-03800-z

Cited by 114 publications

(106 citation statements)

References 42 publications

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“…Very recently, cGAS-like receptors (cGLRs) were characterized as innate immune receptors in Drosophila melanogaster and surprisingly were identified as RNA binders. Crystal structure studies identified differences in the ligand binding surface between cGLR1 and c-GAS that could explain the differences in nucleic acid binding preferences [31,32]. These new findings highlight that our understanding of all the potential ligands for cGAS as well as what guides the selectivity is likely only the tip of the iceberg.…”

Section: Dna Sensing-cgas Pathwaymentioning

confidence: 86%

Sensing Stemness

Bowman

Trompouki

2021

Curr Stem Cell Rep

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Purpose of Review Hematopoietic stem cells (HSCs) are formed embryonically during a dynamic developmental process and later reside in adult hematopoietic organs in a quiescent state. In response to their changing environment, HSCs have evolved diverse mechanisms to cope with intrinsic and extrinsic challenges. This review intends to discuss how HSCs and other stem cells co-opted DNA and RNA innate immune pathways to fine-tune developmental processes. Recent Findings Innate immune receptors for nucleic acids like the RIG-I-like family receptors and members of DNA sensing pathways are expressed in HSCs and other stem cells. Even though the “classic” role of these receptors is recognition of foreign DNA or RNA from pathogens, it was recently shown that cellular transposable element (TE) RNA or R-loops activate such receptors, serving as endogenous triggers of inflammatory signaling that can shape HSC formation during development and regeneration. Summary Endogenous TEs and R-loops activate RNA and DNA sensors, which trigger distinct inflammatory signals to fine-tune stem cell decisions. This phenomenon could have broad implications for diverse somatic stem cells, for a variety of diseases and during aging.

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Section: Dna Sensing-cgas Pathwaymentioning

confidence: 86%

Sensing Stemness

Bowman

Trompouki

2021

Curr Stem Cell Rep

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“…We have demonstrated that As CdnG synthesizes 3′,2′-cGAMP in vitro, and 3′,2′-cGAMP is the biological signaling molecule that activates both As Cap5 and Ll Cap5 for DNA degradation. While this manuscript was in review, two publications revealed enzymatic synthesis of 3′,2′-cGAMP by cGAS-like receptors from Drosophila 22 , 23 . In addition, we have also carried out structural and mutational studies of Cap5, which provide structural insight into Cap5, as well as the mode of action of the SAVED domain activating Cap5 for DNA degradation.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms of the CdnG-Cap5 antiphage defense system employing 3′,2′-cGAMP as the second messenger

et al. 2021

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Cyclic-oligonucleotide-based antiphage signaling systems (CBASS) are diverse and abundant in bacteria. Here, we present the biochemical and structural characterization of two CBASS systems, composed of CdnG and Cap5, from Asticcacaulis sp. and Lactococcus lactis. We show that CdnG from Asticcacaulis sp. synthesizes 3′,2′-cGAMP in vitro, and 3′,2′-cGAMP is the biological signaling molecule that activates Cap5 for DNA degradation. Crystal structures of Cap5, together with the SAVED domain in complex with 3′,2′-cGAMP, provide insight into the architecture of Cap5 as well as molecular recognition of 3′,2′-cGAMP by the SAVED domain of Cap5. Amino acid conservation of the SAVED domain of Cap5, together with mutational studies, led us to propose a mechanism of Back-to-Front stacking of two SAVED domains, mediated by 3′,2′-cGAMP, to activate HNH nuclease domain for DNA degradation. This study of the most abundant CBASS system provides insights into the mechanisms employed by bacteria in their conflicts against phage.

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“…To our knowledge, this is the first time that a member of the G clade of CD-NTases has been biochemically characterized, and the first observation of enzymatic synthesis of 3’,2’-cGAMP in bacteria. While this manuscript was in review, two publications revealed enzymatic synthesis of 3’,2’-cGAMP by cGAS-like receptors from Drosophila 22,23 . In addition, we have also carried out structural and mutational studies of Cap5, which provide structural insight into Cap5 as well as the mode of action of the SAVED domain activating Cap5 for DNA degradation.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms of the CdnG-Cap5 antiphage defense system employing 3’,2’-cGAMP as the second messenger

Fatma

Chakravarti

Zeng

et al. 2021

Preprint

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Cyclic-oligonucleotide-based antiphage signaling systems (CBASS) are diverse and abundant in bacteria. Here, we present biochemical and structural characterization of two CBASS systems, composed of CdnG and Cap5, from Asticcacaulis sp. and Lactococcus lactis. We show that CdnG from Asticcacaulis sp. synthesizes 3′,2′-cGAMP in vitro, and 3′,2′-cGAMP is the biological signaling molecule that activates Cap5 for DNA degradation. Crystal structures of Cap5, together with the SAVED domain in complex with 3′,2′-cGAMP, provide insight into the architecture of Cap5 as well as molecular recognition of 3′,2′-cGAMP by the SAVED domain of Cap5. Amino acid conservation of the SAVED domain of Cap5, together with mutational studies, led us to propose a novel mechanism of Back-to-Front stacking of two SAVED domains, mediated by 3′,2′-cGAMP, to activate HNH nuclease domain for DNA degradation. Our study of the most abundant CBASS system provides new insight into mechanisms employed by bacteria in their conflicts against phage.

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Two cGAS-like receptors induce antiviral immunity in Drosophila

Cited by 114 publications

References 42 publications

Sensing Stemness

Sensing Stemness

Molecular mechanisms of the CdnG-Cap5 antiphage defense system employing 3′,2′-cGAMP as the second messenger

Molecular mechanisms of the CdnG-Cap5 antiphage defense system employing 3’,2’-cGAMP as the second messenger

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