TIR domains of plant immune receptors are NAD+-cleaving enzymes that promote cell death
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.
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
References and Notes
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Science
Volume 365 | Issue 6455
23 August 2019
23 August 2019
Copyright
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
This is an article distributed under the terms of the Science Journals Default License.
Submission history
Received: 28 February 2019
Accepted: 10 July 2019
Published in print: 23 August 2019
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.
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Funding Information
National Science Foundation: IOS-1758400
National Science Foundation: IOS-1758400
National Institutes of Health: RF1AG013730
National Institutes of Health: R01NS087632
National Institutes of Health: R01NS087632
National Institutes of Health: F32GM108226
National Institutes of Health: GM107444
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