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