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NAD depletion as pathogen response

One way that plants respond to pathogen infection is by sacrificing the infected cells. The nucleotide-binding leucine-rich repeat immune receptors responsible for this hypersensitive response carry Toll/interleukin-1 receptor (TIR) domains. In two papers, Horsefield et al. and Wan et al. report that these TIR domains cleave the metabolic cofactor nicotinamide adenine dinucleotide (NAD+) as part of their cell-death signaling in response to pathogens. Similar signaling links mammalian TIR-containing proteins to NAD+ depletion during Wallerian degeneration of neurons.
Science, this issue p. 793, p. 799

Abstract

Plant nucleotide-binding leucine-rich repeat (NLR) immune receptors activate cell death and confer disease resistance by unknown mechanisms. We demonstrate that plant Toll/interleukin-1 receptor (TIR) domains of NLRs are enzymes capable of degrading nicotinamide adenine dinucleotide in its oxidized form (NAD+). Both cell death induction and NAD+ cleavage activity of plant TIR domains require known self-association interfaces and a putative catalytic glutamic acid that is conserved in both bacterial TIR NAD+-cleaving enzymes (NADases) and the mammalian SARM1 (sterile alpha and TIR motif containing 1) NADase. We identify a variant of cyclic adenosine diphosphate ribose as a biomarker of TIR enzymatic activity. TIR enzymatic activity is induced by pathogen recognition and functions upstream of the genes enhanced disease susceptibility 1 (EDS1) and N requirement gene 1 (NRG1), which encode regulators required for TIR immune function. Thus, plant TIR-NLR receptors require NADase function to transduce recognition of pathogens into a cell death response.
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Supplementary Material

Summary

Materials and Methods
Figs. S1 to S11
Tables S1 to S3
References
Data S1 to S3

Resources

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References and Notes

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Information & Authors

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Published In

Science
Volume 365 | Issue 6455
23 August 2019

Submission history

Received: 28 February 2019
Accepted: 10 July 2019
Published in print: 23 August 2019

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Acknowledgments

We thank S. Grant and M. Redinbo for careful reading and discussion of the manuscript. We thank B. Staskawicz for sharing N. benthamiana eds1 and nrg1 mutants. We thank B. Kobe for sharing the sequence of the SARM1 SAM domain pentamutant. We thank K. Simburger and T. Fahrner for technical assistance. We thank C. Argueso and D. Bush for use of facilities. We thank B. Staskawicz, K. H. Sohn, and F. El Kasmi for plasmids. Funding: This work was supported by the National Science Foundation (grant IOS-1758400 to J.L.D. and M.T.N.) and National Institutes of Health (grants GM107444 to J.L.D., RF1AG013730 to J.M., and R01NS087632 to J.M. and A.D.). J.L.D. is a Howard Hughes Medical Institute (HHMI) Investigator. M.T.N. was supported by startup funds from Colorado State University. R.G.A. was supported by an NIH Ruth L. Kirschstein NRSA fellowship (F32GM108226). K.E. was an HHMI Medical Research Fellow. F.M. is supported by a grant from the Gordon and Betty Moore Foundation (GBMF4725) to the Two Blades Foundation. Author contributions: L.W., K.E., R.G.A., J.M., J.L.D., and M.T.N. conceived and designed the study. L.W., K.E., R.G.A., Y.S., F.M., E.C., and M.T.N. generated data. L.W., K.E., J.M., J.L.D., and M.T.N. wrote the initial manuscript. All authors edited the final version of the manuscript. Competing interests: J.M. and Y.S. may derive income from licensing technology to ChromaDex. J.M. and A.D. are cofounders and scientific advisors of Disarm Therapeutics. K.E., Y.S., A.D., and J.M. may derive income from licensing of technology to Disarm Therapeutics. Data and materials availability: All data are available in the manuscript or the supplementary materials.

Authors

Affiliations

Department of Biology and Howard Hughes Medical Institute, University of North Carolina, Chapel Hill, NC 27599, USA.
Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Ryan G. Anderson
Department of Biology and Howard Hughes Medical Institute, University of North Carolina, Chapel Hill, NC 27599, USA.
Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Department of Biology and Howard Hughes Medical Institute, University of North Carolina, Chapel Hill, NC 27599, USA.
Center for Research in Agricultural Genomics (CRAG), CSIC-IRTA-UAB-UB, 08193 Barcelona, Spain.
Department of Biology and Howard Hughes Medical Institute, University of North Carolina, Chapel Hill, NC 27599, USA.
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523, USA.
Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University School of Medicine, St. Louis, MO 63110, USA.
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, USA.
Department of Biology and Howard Hughes Medical Institute, University of North Carolina, Chapel Hill, NC 27599, USA.
Department of Biology, Colorado State University, Fort Collins, CO 80523, USA.

Funding Information

Notes

*
These authors contributed equally to this work.
†Corresponding author. Email: [email protected] (M.T.N.); [email protected] (J.L.D.); [email protected] (J.M.)

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