The Toll/interleukin-1 receptor (TIR) domain is the signature signalling motif of innate immunity, with essential roles in innate immune signalling in bacteria, plants, and animals. TIR domains canonically function as scaffolds, with stimulus-dependent multimerization generating binding sites for signalling molecules such as kinases and ligases that activate downstream immune mechanisms. Recent studies have dramatically expanded our understanding of the TIR domain, demonstrating that the primordial function of the TIR domain is to metabolize NAD⁺. Mammalian SARM1, the central executioner of pathological axon degeneration, is the founding member of the TIR-domain class of NAD⁺ hydrolases. This unexpected NADase activity of TIR domains is evolutionarily conserved, with archaeal, bacterial, and plant TIR domains all sharing this catalytic function. Moreover, this enzymatic activity is essential for the innate immune function of these proteins. These evolutionary relationships suggest a link between SARM1 and ancient self-defense mechanisms that has only been strengthened by the recent discovery of the SARM1 activation mechanism which, we will argue, is strikingly similar to bacterial toxin-antitoxin systems. In this brief review we will describe the regulation and function of SARM1 in programmed axon self-destruction, and highlight the parallels between the SARM1 axon degeneration pathway and bacterial innate immune mechanisms.

Toll/白介素-1 受体 (TIR) 结构域是先天免疫的标志性信号基序，在细菌、植物和动物的先天免疫信号传导中发挥重要作用。 TIR 结构域通常充当支架，通过刺激依赖性多聚化为信号分子（例如激活下游免疫机制的激酶和连接酶）生成结合位点。最近的研究极大地扩展了我们对 TIR 结构域的理解，证明 TIR 结构域的原始功能是代谢 NAD ⁺ 。哺乳动物 SARM1 是病理性轴突变性的中央执行者，是 NAD ⁺水解酶 TIR 结构域类的创始成员。 TIR 结构域这种意想不到的 NADase 活性在进化上是保守的，古细菌、细菌和植物 TIR 结构域都共享这种催化功能。此外，这种酶活性对于这些蛋白质的先天免疫功能至关重要。这些进化关系表明 SARM1 和古代自卫机制之间的联系，最近发现的 SARM1 激活机制进一步加强了这种联系，我们认为，SARM1 激活机制与细菌毒素-抗毒素系统惊人地相似。在这篇简短的综述中，我们将描述 SARM1 在程序性轴突自毁中的调节和功能，并强调 SARM1 轴突变性途径与细菌先天免疫机制之间的相似之处。