A Cell-Permeant Mimetic of NMN Activates SARM1 to Produce Cyclic ADP-Ribose and Induce Non-apoptotic Cell Death
A Cell-Permeant Mimetic of NMN Activates SARM1 to Produce Cyclic ADP-Ribose and Induce Non-apoptotic Cell Death
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NMN 的细胞渗透模拟物激活 SARM1 产生环状 ADP-核糖并诱导非凋亡细胞死亡。
DOI：
10.1016/j.isci.2019.05.001
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发表时间：
2019-05-31
期刊：
影响因子：
5.8
通讯作者：
Zhao, Yong Juan
中科院分区：
文献类型：
--
作者：
Zhao, Zhi Ying;Xie, Xu Jie;Zhao, Yong Juan
SARM 1是一种NAD利用酶，调节轴突变性。我们发现，CZ-48，NMN的细胞渗透模拟物，在体外和细胞内激活SARM 1，使NAD环化并产生Ca 2+信使cADPR，其效率与NMN相似。敲除NMN-腺苷酰转移酶可提高细胞NMN水平，并激活SARM 1产生cADPR，证实NMN是其内源性激活剂。确定了CZ-48的活化作用和细胞渗透性的决定因素。CZ-48通过自身抑制结构域的构象变化和其催化结构域的二聚化来激活SARM 1。SARM 1的催化作用与CD 38相似，尽管没有序列相似性。两者都催化类似的反应，但SARM 1具有更高的NAD环化活性，使其在提高cADPR方面更有效。CZ-48选择性地起作用，激活SARM 1但抑制CD 38。在SARM 1过表达细胞中，CZ-48升高cADPR，耗尽NAD和ATP，并诱导非凋亡死亡。CZ-48是细胞中SARM 1功能的特异性调节剂。
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 Ca2+ 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.