@article{8c383efba3ab4af1a14d21f869564b89,
title = "cGLRs are a diverse family of pattern recognition receptors in innate immunity",
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.",
keywords = "STING, cGAS, cGLR, cyclic dinucleotides, innate immunity, pattern recognition receptor",
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.}",
note = "Funding Information: The authors are grateful to J. Eaglesham and members of the Kranzusch lab for helpful comments and discussion. The authors thank C. Deutscher (Biolog) for expert technical assistance with synthetic cyclic dinucleotide purifications, J. Jamieson and S. Ratcliff (Rutgers University) for assistance with animal care and sampling, and Y. Fang (Boston University) for technical support with data visualization. The work was funded by grants to P.J.K. from the Pew Biomedical Scholars program, the Burroughs Wellcome Fund PATH program, the Richard and Susan Smith Family Foundation, The Mathers Foundation, The Mark Foundation for Cancer Research, the Cancer Research Institute, the Parker Institute for Cancer Immunotherapy, the DFCI-Novartis Drug Discovery Program, and the National Institutes of Health (1DP2GM146250-01). Y.L. is supported as a Benacerraf Fellow in Immunology and a Parker Institute for Cancer Immunotherapy (PICI) Fellow, K.M.S. is supported as an NCI F99 Graduate Fellow NIH 1F99CA274660-01, B.R.M. was supported as a Ruth L. Kirschstein NRSA Postdoctoral Fellow NIH F32GM133063, and C.C.d.O.M. was supported as a Cancer Research Institute/Eugene V. Weissman Fellow. Research in A.S.-P. group was supported by the European Research Council (ERC-StG 851647) and the Spanish Ministry of Science and Innovation (PID2021-124757NB-I00), S.L. is supported by a MSCA postdoctoral fellowship (101065294), and A.E. is supported by FPI PhD fellowships from the Spanish Ministry of Science and Innovation. Z.W. and X.G. were supported by USDA Animal Health Project NJ30401. X-ray data were collected at the Northeastern Collaborative Access Team beamlines 24-ID-C and 24-ID-E (P30 GM124165), and a Pilatus detector (S10RR029205), an Eiger detector (S10OD021527), and the Argonne National Laboratory Advanced Photon Source (DE-AC02-06CH11357) were used. Experiments were designed and conceived by Y.L. K.M.S. B.R.M. C.C.d.O.M. and P.J.K. cGLR bioinformatic analysis and initial screen was performed by Y.L. K.M.S, B.R.M. C.C.d.O.M. and P.J.K. Biochemical and nucleotide second messenger analysis experiments were performed by Y.L. with assistance from H.C.T. K.M.S. B.R.M. and J.L. Crystallography experiments were performed by Y.L. with assistance from H.C.T. B.R.M. K.S.M. and J.L. Animal experiments were performed by S.L. Z.W. X.G. and T.M.; and bioinformatics analysis was performed by A.E. and A.S.-P. Synthetic nucleotide product synthesis and characterization experiments were performed by D.K. and F.S. The manuscript was written by Y.L. and P.J.K. All authors contributed to editing the manuscript and support the conclusions. D.K. and F.S. are employed at Biolog Life Science Institute GmbH & Co. KG, which sells 3′3′-cUA and may sell 2′3′-cUA as research tools. Funding Information: The authors are grateful to J. Eaglesham and members of the Kranzusch lab for helpful comments and discussion. The authors thank C. Deutscher (Biolog) for expert technical assistance with synthetic cyclic dinucleotide purifications, J. Jamieson and S. Ratcliff (Rutgers University) for assistance with animal care and sampling, and Y. Fang (Boston University) for technical support with data visualization. The work was funded by grants to P.J.K. from the Pew Biomedical Scholars program , the Burroughs Wellcome Fund PATH program , the Richard and Susan Smith Family Foundation , The Mathers Foundation , The Mark Foundation for Cancer Research , the Cancer Research Institute , the Parker Institute for Cancer Immunotherapy , the DFCI-Novartis Drug Discovery Program , and the National Institutes of Health ( 1DP2GM146250-01 ). Y.L. is supported as a Benacerraf Fellow in Immunology and a Parker Institute for Cancer Immunotherapy (PICI) Fellow, K.M.S. is supported as an NCI F99 Graduate Fellow NIH 1F99CA274660-01 , B.R.M. was supported as a Ruth L. Kirschstein NRSA Postdoctoral Fellow NIH F32GM133063 , and C.C.d.O.M. was supported as a Cancer Research Institute/Eugene V. Weissman Fellow. Research in A.S.-P. group was supported by the European Research Council ( ERC-StG 851647 ) and the Spanish Ministry of Science and Innovation ( PID2021-124757NB-I00 ), S.L. is supported by a MSCA postdoctoral fellowship ( 101065294 ), and A.E. is supported by FPI PhD fellowships from the Spanish Ministry of Science and Innovation . Z.W. and X.G. were supported by USDA Animal Health Project NJ30401 . X-ray data were collected at the Northeastern Collaborative Access Team beamlines 24-ID-C and 24-ID-E ( P30 GM124165 ), and a Pilatus detector ( S10RR029205 ), an Eiger detector ( S10OD021527 ), and the Argonne National Laboratory Advanced Photon Source ( DE-AC02-06CH11357 ) were used. Publisher Copyright: {\textcopyright} 2023 The Author(s)",
year = "2023",
month = jul,
day = "20",
doi = "https://doi.org/10.1016/j.cell.2023.05.038",
language = "English",
volume = "186",
pages = "3261--3276.e20",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "15",
}