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【前沿】FASEB J.:RNA编辑酶在细胞分泌过程中的调控功能
2010-10-17 15:58   发布范围:公开

最近美国《实验生物学联合会会刊》 (The FASEB Journal)发表了中科院上海生科院营养所刘勇研究组在RNA编辑与细胞分泌功能研究方面所取得的最新进展—“Deficiency in RNA editing enzyme ADAR2 impairs regulated exocytosis”。

RNA编辑(RNA editing)泛指真核细胞中对RNA分子在转录后进行再加工和修饰的过程,能够使基因编码的遗传信息在RNA水平上进一步产生多样性与可塑性。RNA腺苷脱氨酶ADAR (Adenosine Deaminase Acting on RNA) 家族的RNA编辑酶ADAR1和ADAR2,能识别特定RNA底物分子中的腺苷(A)并催化其水解脱氨成为肌苷(I),因此RNA编辑可以改变mRNA所编码蛋白质分子的功能活性,影响mRNA的稳定性,或参与microRNA的加工成熟以及改变microRNA对其底物RNA分子的识别等一系列重要的生物学过程。在中枢神经系统中,A-to-I编辑通过选择性调节关键离子通道和神经递质受体的功能特性,从而发挥及其重要的生理学功能。刘勇研究组此前发表的研究工作显示,在胰岛β细胞中ADAR2介导的RNA编辑过程受机体营养与能量代谢状况的调控(Gan et al. JBC 281:33386-94,2006),但ADAR2在专职分泌的细胞中行使怎样的细胞生物学功能却依然不明了。

为进一步探寻ADAR介导的RNA编辑在代谢平衡相关调节过程中的功能,刘勇研究组博士研究生杨柳、赵丽韵等通过研究发现,特异性地抑制ADAR2编辑酶的表达,能够显着削弱葡萄糖刺激下β细胞或胰岛中的胰岛素分泌,也同样导致PC12细胞分泌能力的缺损,而且ADAR2对细胞分泌过程的影响依赖于其编辑酶的催化活性。在β细胞中,ADAR2的缺失虽然不影响胞内钙离子的动员激活,却显着削弱由钙离子激发的细胞膜电容变化,还导致锚定于细胞膜上胰岛素分泌囊泡数量的降低,并伴随着参与细胞胞吐过程的重要调节因子Munc18-1和 Synaptotagmin-7其表达水平的下调。这些结果表明,ADAR2编辑酶介导的RNA编辑作为一种基因转录后的调控机制参与了细胞胞吐这一过程的调节。这为深入了解RNA编辑在中枢神经或外周组织的细胞分泌、代谢平衡等方面所发挥的作用提供了机制上的新线索。

此项工作得到国家973研究计划、国家自然科学基金委重点项目、上海市科委和中科院知识创新工程的经费资助。(生物谷Bioon.com)

生物谷推荐英文摘要:

The FASEB Journal. 2010;24:3720-3732. doi:10.1096/fj.09-152363.

Deficiency in RNA editing enzyme ADAR2 impairs regulated exocytosis
Liu Yang*,1, Liyun Zhao*,1, Zhenji Gan*,2, Zixuan He,3, Jingyue Xu, Xiang Gao, Xiaorui Wang, Weiping Han, Liangyi Chen, Tao Xu, Wenjun Li*,4 and Yong Liu*,4

* Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences (SIBS), Shanghai, China;
 Institute of Biophysics, Chinese Academy of Sciences (CAS), Beijing, China;
 Model Animal Research Center, Nanjing University, Nanjing, China; and
 Singapore Bioimaging Consortium, Agency for Science, Technology, and Research (A*STAR), Singapore

Mammalian RNA editing catalyzed by adenosine deaminases acting on RNA (ADARs) ADAR1 and ADAR2 plays pivotal roles in the brain through functional modifications of neurotransmitter receptors and ion channels. We have demonstrated previously that RNA editing by ADAR2 is regulated metabolically in pancreatic β cells. To investigate the cellular functions of ADAR2 in professional secretory cells, we studied the effects of ADAR2 knockdown on regulated exocytosis. Selective knockdown of ADAR2 expression markedly impaired glucose-stimulated insulin secretion in the rat insulinoma INS-1 cells and primary pancreatic islets and significantly diminished KCl-stimulated secretion of exogenous human growth hormone or endogenous chromogranin B protein in the rat adrenal pheochromocytoma PC12 cells. Notably, restored overexpression of catalytically active but not editing-deficient mutant ADAR2 could rescue the impairment in stimulated secretion from ADAR2 knockdown cells. Moreover, ADAR2 suppression significantly attenuated Ca2+-evoked membrane capacitance increases and appreciably reduced the number of membrane-docked insulin granules in INS-1 cells. Interestingly, the secretory defects resulting from ADAR2 deficiency were coupled to decreased expression of Munc18-1 and synaptotagmin-7, two key molecules in the regulation of vesicle exocytosis. Thus, these findings reveal an important aspect of ADAR2 actions in regulated exocytosis, implicating RNA editing in the control of cellular secretory machinery.—Yang, L., Zhao, L., Gan, Z., He, Z., Xu, J., Gao, X., Wang, X., Han, W., Chen, L., Xu, T., Li, W., Liu, Y. Deficiency in RNA editing enzyme ADAR2 impairs regulated exocytosis.

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