The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD(+) Cleavage Activity that Promotes Pathological Axonal Degeneration.
The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD(+) Cleavage Activity that Promotes Pathological Axonal Degeneration.
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DOI：
10.1016/j.neuron.2017.02.022
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发表时间：
2017-03-22
期刊：
影响因子：
16.2
通讯作者：
Milbrandt J
中科院分区：
文献类型：
--
作者：
Essuman K;Summers DW;Sasaki Y;Mao X;DiAntonio A;Milbrandt J
轴突变性是许多神经系统疾病的早期和显著特征。SARM 1是轴突变性途径的中心执行者，其最终导致轴突NAD+的消耗;然而，潜在的NAD+消耗酶的身份尚不清楚。在这里，在使用来自哺乳动物细胞、细菌和无细胞蛋白翻译系统的纯化蛋白的一系列实验中，我们表明SARM 1-TIR结构域本身具有固有的NAD酶活性-将NAD+切割成ADP核糖（ADPR）、环状ADPR和烟酰胺，烟酰胺作为该酶的反馈抑制剂。使用创伤性和长春新碱诱导的神经元损伤模型，我们证明了在轴突中需要全长SARM 1的NAD酶活性来促进损伤后轴突NAD+耗尽和轴突变性。因此，SARM 1酶代表了轴突病的新治疗靶点。此外，广泛使用的TIR结构域是可以具有酶活性的蛋白质基序。Essuman等人证明SARM 1的TIR结构域是一种消耗轴突NAD+以诱导病理性轴突损失的酶。这种酶活性代表了许多以轴突变性为特征的神经系统疾病的新治疗靶点。更广泛地说，这项研究表明TIR结构域可以具有酶功能。
Axonal degeneration is an early and prominent feature of many neurological disorders. SARM1 is the central executioner of the axonal degeneration pathway that culminates in depletion of axonal NAD+; yet the identity of the underlying NAD+ depleting enzyme(s) is unknown. Here, in a series of experiments using purified proteins from mammalian cells, bacteria, and a cell-free protein translation system, we show that the SARM1-TIR domain itself has intrinsic NADase activity – cleaving NAD+ into ADP Ribose (ADPR), cyclic ADPR, and Nicotinamide, with Nicotinamide serving as a feedback inhibitor of the enzyme. Using traumatic and vincristine-induced injury models in neurons, we demonstrate that the NADase activity of full-length SARM1 is required in axons to promote axonal NAD+ depletion and axonal degeneration after injury. Hence, the SARM1 enzyme represents a novel therapeutic target for axonopathies. Moreover, the widely utilized TIR-domain is a protein motif that can possess enzymatic activity. Essuman et al. demonstrate that the TIR domain of SARM1 is an enzyme that depletes axonal NAD+ to induce pathological axon loss. This enzymatic activity represents a novel therapeutic target for many neurological conditions characterized by axonal degeneration. More broadly, this study shows that TIR domains can possess enzymatic function.
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