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

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.The work was supported by the National Health and Medical Research Council (NHMRC grants 1107804 and 1160570 to B.K. and T.V.. 1071659 to B.K., and 1108859 to T.V.), and the Australian Research Council (ARC grants DP160102244 and DP190102526 to B.K. and P.N.D.). B.K. was an NHMRC Principal Research Fellow (1110971) and ARC Laureate Fellow (FL180100109). T.V. received ARC DECRA (DE170100783) funding and S.J.W. received ARC DECRA DE160100893 funding. J.C. received a Chinese Scholarship Council (CSC) postgraduate scholarship. Y.S. was a Griffith University postdoctoral fellow. J.G. was supported by the UK Medical Research Council and M.P.C. was supported by the John and Lucille van Geest Foundation. M.K.M. was supported by the Australian Government Research Training Program (RTP)