cGLRs are a diverse family of pattern recognition receptors in innate immunity

Yao Li; Kailey M. Slavik; Hunter C. Toyoda; Benjamin R. Morehouse; Carina C. de Oliveira Mann; Anamaria Elek; Shani Levy; Zhenwei Wang; Kepler S. Mears; Jingjing Liu; Dmitry Kashin; Ximing Guo; Tali Mass; Arnau Sebé-Pedrós; Frank Schwede; Philip J. Kranzusch

doi:https://doi.org/10.1016/j.cell.2023.05.038

cGLRs are a diverse family of pattern recognition receptors in innate immunity

Yao Li, Kailey M. Slavik, Hunter C. Toyoda, Benjamin R. Morehouse, Carina C. de Oliveira Mann, Anamaria Elek, Shani Levy, Zhenwei Wang, Kepler S. Mears, Jingjing Liu, Dmitry Kashin, Ximing Guo, Tali Mass, Arnau Sebé-Pedrós, Frank Schwede, Philip J. Kranzusch

Department of Marine Biology

University of Haifa

Research output: Contribution to journal › Article › peer-review

Abstract

Cyclic GMP-AMP synthase (cGAS) is an enzyme in human cells that controls an immune response to cytosolic DNA. Upon binding DNA, cGAS synthesizes a nucleotide signal 2′3′-cGAMP that activates STING-dependent downstream immunity. Here, we discover that cGAS-like receptors (cGLRs) constitute a major family of pattern recognition receptors in innate immunity. Building on recent analysis in Drosophila, we identify >3,000 cGLRs present in nearly all metazoan phyla. A forward biochemical screening of 150 animal cGLRs reveals a conserved mechanism of signaling including response to dsDNA and dsRNA ligands and synthesis of isomers of the nucleotide signals cGAMP, c-UMP-AMP, and c-di-AMP. Combining structural biology and in vivo analysis in coral and oyster animals, we explain how synthesis of distinct nucleotide signals enables cells to control discrete cGLR-STING signaling pathways. Our results reveal cGLRs as a widespread family of pattern recognition receptors and establish molecular rules that govern nucleotide signaling in animal immunity.

Original language	American English
Pages (from-to)	3261-3276.e20
Journal	Cell
Volume	186
Issue number	15
DOIs	https://doi.org/10.1016/j.cell.2023.05.038
State	Published - 20 Jul 2023

Keywords

STING
cGAS
cGLR
cyclic dinucleotides
innate immunity
pattern recognition receptor

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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https://doi.org/10.1016/j.cell.2023.05.038

Cite this

Li, Y., Slavik, K. M., Toyoda, H. C., Morehouse, B. R., de Oliveira Mann, C. C., Elek, A., Levy, S., Wang, Z., Mears, K. S., Liu, J., Kashin, D., Guo, X., Mass, T., Sebé-Pedrós, A., Schwede, F., & Kranzusch, P. J. (2023). cGLRs are a diverse family of pattern recognition receptors in innate immunity. Cell, 186(15), 3261-3276.e20. https://doi.org/10.1016/j.cell.2023.05.038

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abstract = "Cyclic GMP-AMP synthase (cGAS) is an enzyme in human cells that controls an immune response to cytosolic DNA. Upon binding DNA, cGAS synthesizes a nucleotide signal 2′3′-cGAMP that activates STING-dependent downstream immunity. Here, we discover that cGAS-like receptors (cGLRs) constitute a major family of pattern recognition receptors in innate immunity. Building on recent analysis in Drosophila, we identify >3,000 cGLRs present in nearly all metazoan phyla. A forward biochemical screening of 150 animal cGLRs reveals a conserved mechanism of signaling including response to dsDNA and dsRNA ligands and synthesis of isomers of the nucleotide signals cGAMP, c-UMP-AMP, and c-di-AMP. Combining structural biology and in vivo analysis in coral and oyster animals, we explain how synthesis of distinct nucleotide signals enables cells to control discrete cGLR-STING signaling pathways. Our results reveal cGLRs as a widespread family of pattern recognition receptors and establish molecular rules that govern nucleotide signaling in animal immunity.",

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author = "Yao Li and Slavik, {Kailey M.} and Toyoda, {Hunter C.} and Morehouse, {Benjamin R.} and {de Oliveira Mann}, {Carina C.} and Anamaria Elek and Shani Levy and Zhenwei Wang and Mears, {Kepler S.} and Jingjing Liu and Dmitry Kashin and Ximing Guo and Tali Mass and Arnau Seb{\'e}-Pedr{\'o}s and Frank Schwede and Kranzusch, {Philip J.}",

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AU - Li, Yao

AU - Slavik, Kailey M.

AU - Toyoda, Hunter C.

AU - Morehouse, Benjamin R.

AU - de Oliveira Mann, Carina C.

AU - Elek, Anamaria

AU - Levy, Shani

AU - Wang, Zhenwei

AU - Mears, Kepler S.

AU - Liu, Jingjing

AU - Kashin, Dmitry

AU - Guo, Ximing

AU - Mass, Tali

AU - Sebé-Pedrós, Arnau

AU - Schwede, Frank

AU - Kranzusch, Philip J.

PY - 2023/7/20

Y1 - 2023/7/20

N2 - Cyclic GMP-AMP synthase (cGAS) is an enzyme in human cells that controls an immune response to cytosolic DNA. Upon binding DNA, cGAS synthesizes a nucleotide signal 2′3′-cGAMP that activates STING-dependent downstream immunity. Here, we discover that cGAS-like receptors (cGLRs) constitute a major family of pattern recognition receptors in innate immunity. Building on recent analysis in Drosophila, we identify >3,000 cGLRs present in nearly all metazoan phyla. A forward biochemical screening of 150 animal cGLRs reveals a conserved mechanism of signaling including response to dsDNA and dsRNA ligands and synthesis of isomers of the nucleotide signals cGAMP, c-UMP-AMP, and c-di-AMP. Combining structural biology and in vivo analysis in coral and oyster animals, we explain how synthesis of distinct nucleotide signals enables cells to control discrete cGLR-STING signaling pathways. Our results reveal cGLRs as a widespread family of pattern recognition receptors and establish molecular rules that govern nucleotide signaling in animal immunity.

AB - Cyclic GMP-AMP synthase (cGAS) is an enzyme in human cells that controls an immune response to cytosolic DNA. Upon binding DNA, cGAS synthesizes a nucleotide signal 2′3′-cGAMP that activates STING-dependent downstream immunity. Here, we discover that cGAS-like receptors (cGLRs) constitute a major family of pattern recognition receptors in innate immunity. Building on recent analysis in Drosophila, we identify >3,000 cGLRs present in nearly all metazoan phyla. A forward biochemical screening of 150 animal cGLRs reveals a conserved mechanism of signaling including response to dsDNA and dsRNA ligands and synthesis of isomers of the nucleotide signals cGAMP, c-UMP-AMP, and c-di-AMP. Combining structural biology and in vivo analysis in coral and oyster animals, we explain how synthesis of distinct nucleotide signals enables cells to control discrete cGLR-STING signaling pathways. Our results reveal cGLRs as a widespread family of pattern recognition receptors and establish molecular rules that govern nucleotide signaling in animal immunity.

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KW - cGAS

KW - cGLR

KW - cyclic dinucleotides

KW - innate immunity

KW - pattern recognition receptor

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DO - https://doi.org/10.1016/j.cell.2023.05.038

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SN - 0092-8674

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SP - 3261-3276.e20

JO - Cell

JF - Cell

IS - 15

ER -

cGLRs are a diverse family of pattern recognition receptors in innate immunity

Abstract

Keywords

All Science Journal Classification (ASJC) codes

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