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The Toll-interleukin-1 receptor (TIR) homology domains were initially identified as modules facilitating protein-protein interactions in Toll-like receptors (TLRs) and interleukin-1 receptors, as noted by Takeda and Akira (2025). Additionally, these domains are recognized as the N-terminal domain of certain plant NLRs, as discussed by Barragan and Weigel (2021).
Recently, it was discovered that multiple Toll-interleukin-1 receptor (TIR) homology domains throughout the tree of life exhibit a shared enzymatic activity, specifically that of Nicotinamide dinucleotide hydrolase (NADase).
The human SARM1 protein serves as an example, as it degrades NAD+ to mediate Wallerian degeneration, which is a regulated cell death mechanism in damaged axons that is not yet fully understood.