Regulation of SIRT 1 mediated NAD dependent deacetylation: A novel role for the multifunctional enzyme CD38
Regulation of SIRT 1 mediated NAD dependent deacetylation: A novel role for the multifunctional enzyme CD38
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DOI：
10.1016/j.bbrc.2006.08.066
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发表时间：
2006-10-13
影响因子：
3.1
通讯作者：
Chini, Eduardo N.
中科院分区：
文献类型：
--
作者：
Aksoy, Pinar;Escande, Carlos;Chini, Eduardo N.
SIRT I 酶是一种 NAD 依赖性脱乙酰酶，与哺乳动物细胞的衰老、细胞保护和能量代谢有关。 SIRT I 的内源活性是如何调节的尚不清楚。 CD38酶是一种多功能酶，能够合成第二信使cADPR、NAADP和ADPR。然而，CD38的主要酶活性是NAD的水解。特别令人感兴趣的是 CD38 存在于内核膜上。在这里，我们研究了 CD38 对 SIRT I 活性的调节。我们认为，通过调节 SIRT1 酶的 NAD 利用率，CD38 可以调节 SIRT1 酶活性。我们观察到，在 CD38 敲除小鼠中，NAD 的组织水平显着增加。我们还观察到，将纯化的重组 SIRT1 酶与 CD38 或野生型小鼠的核提取物一起孵育，会导致其活性显着受到抑制。相比之下，SIRT I 与 CD38 敲除小鼠的细胞提取物一起孵育则没有效果。此外，与野生型核提取物相比，CD38 敲除小鼠的核提取物中 SIRT1 的内源活性高出数倍。最后，CD38 敲除小鼠组织中 SIRT1 底物 P53 的体内脱乙酰作用增加。我们的数据支持这样一个新概念：核 CD38 是细胞/核 NAD 水平和 SIRT1 活性的主要调节因子。这些发现对于理解调节细胞内 NAD 水平、能量稳态以及 SIRT 酶调节的衰老和细胞保护的基本机制具有重要意义。 (c) 2006 Elsevier Inc. 保留所有权利。
The SIRT I enzyme is a NAD dependent deacetylase implicated in ageing, cell protection, and energy metabolism in mammalian cells. How the endogenous activity of SIRT I is modulated is not known. The enzyme CD38 is a multifunctional enzyme capable of synthesis of the second messenger, cADPR, NAADP, and ADPR. However, the major enzymatic activity of CD38 is the hydrolysis of NAD. Of particular interest is the fact that CD38 is present on the inner nuclear membrane. Here, we investigate the modulation of the SIRT I activity by CD38. We propose that by modulating availability of NAD to the SIRT1 enzyme, CD38 may regulate SIRT1 enzymatic activity. We observed that in CD38 knockout mice, tissue levels of NAD are significantly increased. We also observed that incubation of purified recombinant SIRT1 enzyme with CD38 or nuclear extracts of wild-type mice led to a significant inhibition of its activity. In contrast, incubation of SIRT I with cellular extract from CD38 knockout mice was without effect. Furthermore, the endogenous activity of SIRT1 was several time higher in nuclear extracts from CD38 knockout mice when compared to wild-type nuclear extracts. Finally, the in vivo deacetylation of the SIRT1 substrate P53 is increased in CD38 knockout mice tissue. Our data support the novel concept that nuclear CD38 is a major regulator of cellular/nuclear NAD level, and SIRT1 activity. These findings have strong implications for understanding the basic mechanisms that modulate intracellular NAD levels, energy homeostasis, as well as ageing and cellular protection modulated by the SIRT enzymes. (c) 2006 Elsevier Inc. All rights reserved.