PDF(Pubmed)
Abstract：
Sterile alpha and TIR motif-containing 1 (SARM1) is a protein involved in programmed death of injured axons. Following axon injury or a drug-induced insult, the TIR domain of SARM1 degrades the essential molecule nicotinamide adenine dinucleotide (NAD+), leading to a form of axonal death called Wallerian degeneration. Degradation of NAD+ by SARM1 is essential for the Wallerian degeneration process, but accumulating evidence suggest that other activities of SARM1, beyond the mere degradation of NAD+, may be necessary for programmed axonal death. In this study we show that the TIR domains of both human and fruit fly SARM1 produce 1\'\'-2\' and 1\'\'-3\' glycocyclic ADP-ribose (gcADPR) molecules as minor products. As previously reported, we observed that SARM1 TIR domains mostly convert NAD+ to ADPR (for human SARM1) or cADPR (in the case of SARM1 from Drosophila melanogaster). However, we now show that human and Drosophila SARM1 additionally convert ~0.1-0.5% of NAD+ into gcADPR molecules. We find that SARM1 TIR domains produce gcADPR molecules both when purified in vitro and when expressed in bacterial cells. Given that gcADPR is a second messenger involved in programmed cell death in bacteria and likely in plants, we propose that gcADPR may play a role in SARM1-induced programmed axonal death in animals.
摘要：
含有无菌α和TIR基序的1（SARM1）是一种与受损轴突的程序性死亡有关的蛋白质。轴突损伤或药物诱导的损伤后，SARM1的TIR结构域降解必需分子烟酰胺腺嘌呤二核苷酸（NAD+），导致一种叫做华勒变性的轴突死亡。SARM1对NAD的降解对于Wallerian变性过程至关重要，但越来越多的证据表明，SARM1的其他活动，除了NAD+的降解，可能是程序性轴突死亡所必需的。在这项研究中，我们表明，人和果蝇SARM1的TIR结构域都产生1个\'\'-2\'和1个\'\'-3\'糖环ADP-核糖（gcADPR）分子作为次要产物。正如以前报道的那样，我们观察到SARM1TIR结构域主要将NAD+转化为ADPR(对于人SARM1)或cADPR(对于来自黑腹果蝇的SARM1)。然而,我们现在表明，人类和果蝇SARM1还将〜0.1-0.5％的NAD转化为gcADPR分子。我们发现SARM1TIR结构域在体外纯化和在细菌细胞中表达时都会产生gcADPR分子。鉴于gcADPR是参与细菌和植物中程序性细胞死亡的第二信使，我们认为gcADPR可能在SARM1诱导的动物程序性轴突死亡中起作用。
