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

Shane Horsefield, Hayden Burdett, Xiaoxiao Zhang, Mohammad K. Manik, Yun Shi, Jian Chen, Tiancong Qi, Jonathan Gilley, Jhih Siang Lai, Maxwell X. Rank, Lachlan W. Casey, Weixi Gu, Daniel J. Ericsson, Gabriel Foley, Robert O. Hughes, Todd Bosanac, Mark Von Itzstein, John P. Rathjen, Jeffrey D. Nanson, Mikael BodenIan B. Dry, Simon J. Williams, Brian J. Staskawicz, Michael P. Coleman, Thomas Ve, Peter N. Dodds, Bostjan Kobe

Research output: Contribution to journalArticlepeer-review

301 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)793-799
Number of pages7
Issue number6455
Publication statusPublished - 23 Aug 2019


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