Cyclic ADP ribose isomers: Production, chemical structures, and immune signaling

Authors

Mohammad K. Manik, The University of Queensland
Yun Shi, Griffith University
Sulin Li, The University of Queensland
Mark A. Zaydman, Washington University School of Medicine in St. Louis
Neha Damaraju, Washington University School of Medicine in St. Louis
Samuel Eastman, University of Nebraska–Lincoln
Thomas G. Smith, University of Nebraska–Lincoln
Weixi Gu, The University of Queensland
Veronika Masic, Griffith University
Tamim Mosaiab, Griffith University
James S. Weagley, Washington University School of Medicine in St. Louis
Steven J. Hancock, The University of Queensland
Eduardo Vasquez, Griffith University
Lauren Hartley-Tassell, Griffith University
Nestoras Kargios, Faculty of Science, Engineering and Medicine
Natsumi Maruta, The University of Queensland
Bryan Y.J. Lim, The University of Queensland
Hayden Burdett, The University of Queensland
Michael J. Landsberg, The University of Queensland
Mark A. Schembri, The University of Queensland
Ivan Prokes, Faculty of Science, Engineering and Medicine
Lijiang Song, Faculty of Science, Engineering and Medicine
Murray Grant, Faculty of Science, Engineering and Medicine
Aaron DiAntonio, Washington University School of Medicine in St. Louis
Jeffrey D. Nanson, The University of Queensland
Ming Guo, University of Nebraska–LincolnFollow
Jeffrey Milbrandt, Washington University School of Medicine in St. Louis
Thomas Ve, Griffith UniversityFollow
Bostjan Kobe, The University of QueenslandFollow

Document Type

Article

Date of this Version

9-30-2022

Citation

Published in Science 377, eadc8969 (2022) 30 September 2022

DOI: 10.1126/science.adc8969

Comments

Copyright © 2022 by the authors; published by American Association for the Advancement of Science. Used by permission.

Abstract

Cyclic adenosine diphosphate (ADP)–ribose (cADPR) isomers are signaling molecules produced by bacterial and plant Toll/interleukin-1 receptor (TIR) domains via nicotinamide adenine dinucleotide (oxidized form) (NAD+) hydrolysis. We show that v-cADPR (2′cADPR) and v2-cADPR (3′cADPR) isomers are cyclized by O-glycosidic bond formation between the ribose moieties in ADPR. Structures of 2′cADPR-producing TIR domains reveal conformational changes that lead to an active assembly that resembles those of Toll-like receptor adaptor TIR domains. Mutagenesis reveals a conserved tryptophan that is essential for cyclization. We show that 3′cADPR is an activator of ThsA effector proteins from the bacterial antiphage defense system termed Thoeris and a suppressor of plant immunity when produced by the effector HopAM1. Collectively, our results reveal the molecular basis of cADPR isomer production and establish 3′cADPR in bacteria as an antiviral and plant immunity–suppressing signaling molecule.