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

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• dc.contributor.author Li, Yao
• dc.contributor.author Slavik, Kailey M.
• dc.contributor.author Toyoda, Hunter C.
• dc.contributor.author Morehouse, Benjamin R.
• dc.contributor.author Oliveira Mann, Carina C. de
• dc.contributor.author Elek, Anamaria
• dc.contributor.author Levy, Shani
• dc.contributor.author Wang, Zhenwei
• dc.contributor.author Mears, Kepler S.
• dc.contributor.author Liu, Jingjing
• dc.contributor.author Kashin, Dmitry
• dc.contributor.author Guo, Ximing
• dc.contributor.author Mass, Tali
• dc.contributor.author Sebé-Pedrós, Arnau
• dc.contributor.author Schwede, Frank
• dc.contributor.author Kranzusch, Philip J.
• dc.date.accessioned 2023-10-17T06:19:24Z
• dc.date.available 2023-10-17T06:19:24Z
• dc.date.issued 2023
• dc.description.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.
• dc.description.sponsorship 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.
• dc.format.mimetype application/pdf
• dc.identifier.citation Li Y, Slavik KM, Toyoda HC, Morehouse BR, de Oliveira Mann CC, Elek A, Levy S, Wang Z, Mears KS, Liu J, Kashin D, Guo X, Mass T, Sebé-Pedrós A, Schwede F, Kranzusch PJ. cGLRs are a diverse family of pattern recognition receptors in innate immunity. Cell. 2023 Jul 20;186(15):3261-76.e20. DOI: 10.1016/j.cell.2023.05.038
• dc.identifier.doi http://dx.doi.org/10.1016/j.cell.2023.05.038
• dc.identifier.issn 0092-8674
• dc.identifier.uri http://hdl.handle.net/10230/58077
• dc.language.iso eng
• dc.publisher Elsevier
• dc.relation.ispartof Cell. 2023 Jul 20;186(15):3261-76.e20
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/851647
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-124757NB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/EC/HE/101065294
• dc.rights © 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword STING
• dc.subject.keyword cGAS
• dc.subject.keyword cGLR
• dc.subject.keyword Cyclic dinucleotides
• dc.subject.keyword Innate immunity
• dc.subject.keyword Pattern recognition receptor
• dc.title cGLRs are a diverse family of pattern recognition receptors in innate immunity
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion