NAD+ cleavage activity by animal and plant TIR domains in cell death pathways

Science. 2019 Aug 23;365(6455):793-799. doi: 10.1126/science.aax1911.

Shane Horsefield ¹, Hayden Burdett ¹, Xiaoxiao Zhang ² ³, Mohammad K Manik ¹, Yun Shi ⁴, Jian Chen ² ³, Tiancong Qi ⁵, Jonathan Gilley ⁶ ⁷, Jhih-Siang Lai ¹, Maxwell X Rank ¹, Lachlan W Casey ¹ ⁸, Weixi Gu ¹, Daniel J Ericsson ⁹, Gabriel Foley ¹, Robert O Hughes ¹⁰, Todd Bosanac ¹⁰, Mark von Itzstein ⁴, John P Rathjen ³, Jeffrey D Nanson ¹, Mikael Boden ¹, Ian B Dry ¹¹, Simon J Williams ³, Brian J Staskawicz ⁵, Michael P Coleman ⁶ ⁷, Thomas Ve ¹² ⁴, Peter N Dodds ¹³, Bostjan Kobe ¹²

Affiliations

1 School of Chemistry and Molecular Biosciences, Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD 4072, Australia.
2 Agriculture and Food, Commonwealth Scientific and Industrial Research Organisation, Canberra, ACT 2601, Australia.
3 Plant Sciences Division, Research School of Biology, The Australian National University, Canberra ACT 2601, Australia.
4 Institute for Glycomics, Griffith University, Southport, QLD 4222, Australia.
5 Department of Plant and Microbial Biology, University of California Berkeley, Berkeley, CA 94720, USA.
6 John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, ED Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK.
7 Babraham Institute, Babraham, Cambridge CB22 3AT, UK.
8 Centre for Microscopy and Microanalysis, University of Queensland, Brisbane, QLD 4072, Australia.
9 Macromolecular Crystallography (MX) Beamlines, Australian Synchrotron, Melbourne, VIC 3168, Australia.
10 Disarm Therapeutics, 400 Technology Square, Cambridge, MA 02139, USA.
11 Agriculture and Food, Commonwealth Scientific and Industrial Research Organisation, Urrbrae, SA 5064, Australia.
12 School of Chemistry and Molecular Biosciences, Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD 4072, Australia. [email protected] [email protected] [email protected].
13 Agriculture and Food, Commonwealth Scientific and Industrial Research Organisation, Canberra, ACT 2601, Australia. [email protected] [email protected] [email protected].

PMID: 31439792 DOI: 10.1126/science.aax1911

Abstract

SARM1 (sterile alpha and TIR motif containing 1) is responsible for depletion of nicotinamide adenine dinucleotide in its oxidized form (NAD⁺) during Wallerian degeneration associated with neuropathies. Plant nucleotide-binding leucine-rich repeat (NLR) immune receptors recognize pathogen effector proteins and trigger localized cell death to restrict pathogen Infection. Both processes depend on closely related Toll/interleukin-1 receptor (TIR) domains in these proteins, which, as we show, feature self-association-dependent NAD⁺ cleavage activity associated with cell death signaling. We further show that SARM1 SAM (sterile alpha motif) domains form an octamer essential for axon degeneration that contributes to TIR domain enzymatic activity. The crystal structures of ribose and NADP⁺ (the oxidized form of nicotinamide adenine dinucleotide phosphate) complexes of SARM1 and plant NLR RUN1 TIR domains, respectively, reveal a conserved substrate binding site. NAD⁺ cleavage by TIR domains is therefore a conserved feature of animal and plant cell death signaling pathways.

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