Zhao Zhi Ying, Xie Xu Jie, Li Wan Hua, Liu Jun, Chen Zhe, Zhang Ben, Li Ting, Li Song Lu, Lu Jun Gang, Zhang Liangren, Zhang Li-He, Xu Zhengshuang, Lee Hon Cheung, Zhao Yong Juan
State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
iScience. 2019 May 31;15:452-466. doi: 10.1016/j.isci.2019.05.001. Epub 2019 May 4.
SARM1, an NAD-utilizing enzyme, regulates axonal degeneration. We show that CZ-48, a cell-permeant mimetic of NMN, activated SARM1 in vitro and in cellulo to cyclize NAD and produce a Ca messenger, cADPR, with similar efficiency as NMN. Knockout of NMN-adenylyltransferase elevated cellular NMN and activated SARM1 to produce cADPR, confirming NMN was its endogenous activator. Determinants for the activating effects and cell permeability of CZ-48 were identified. CZ-48 activated SARM1 via a conformational change of the auto-inhibitory domain and dimerization of its catalytic domain. SARM1 catalysis was similar to CD38, despite having no sequence similarity. Both catalyzed similar set of reactions, but SARM1 had much higher NAD-cyclizing activity, making it more efficient in elevating cADPR. CZ-48 acted selectively, activating SARM1 but inhibiting CD38. In SARM1-overexpressing cells, CZ-48 elevated cADPR, depleted NAD and ATP, and induced non-apoptotic death. CZ-48 is a specific modulator of SARM1 functions in cells.
SARM1是一种利用NAD的酶，可调节轴突退变。我们发现，CZ-48是一种可穿透细胞的NMN模拟物，在体外和细胞内均可激活SARM1，使其将NAD环化并产生一种钙信使分子cADPR，其效率与NMN相似。敲除NMN-腺苷酸转移酶可提高细胞内NMN水平并激活SARM1以产生cADPR，证实NMN是其内源性激活剂。我们确定了CZ-48激活作用和细胞通透性的决定因素。CZ-48通过自抑制结构域的构象变化及其催化结构域的二聚化来激活SARM1。尽管SARM1与CD38没有序列相似性，但其催化作用与CD38相似。两者催化的反应组组相似，但SARM1具有更高的NAD环化活性，使其在提高cADPR方面更有效。CZ-48具有选择性作用，可激活SARM1但抑制CD38。在过表达SARM1的细胞中，CZ-48可提高cADPR水平，消耗NAD和ATP，并诱导非凋亡性死亡。CZ-48是细胞中SARM1功能的特异性调节剂。
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