Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase
Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase
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DOI：
10.1074/jbc.m705488200
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发表时间：
2007-11-16
影响因子：
4.8
通讯作者：
Verdin, Eric
中科院分区：
文献类型：
--
作者：
Ahuja, Nidhi;Schwer, Bjoern;Verdin, Eric
Sirtuins是酵母转录抑制因子Sir2p的同源物，从细菌到人类都是保守的。我们报道，人类SIRT4定位于线粒体。SIRT4是一种基质蛋白，在进入线粒体后在第28个氨基酸处被切割。质谱分析与SIRT4共免疫沉淀蛋白鉴定胰岛素降解酶和ADP/ATP载体蛋白ANT2和ANT3。SIRT4没有组蛋白去乙酰化酶活性，但在组蛋白和牛血清白蛋白上具有有效的adp -核糖基转移酶的功能。SIRT4在朗格汉斯胰岛中表达，并与表达胰岛素的β细胞共定位。产生胰岛素的INS-1E细胞中SIRT4的消耗导致胰岛素分泌增加，以响应葡萄糖。这些观察结果确定了线粒体SIRT4在胰岛素分泌调节中的新作用。
Sirtuins are homologues of the yeast transcriptional repressor Sir2p and are conserved from bacteria to humans. We report that human SIRT4 is localized to the mitochondria. SIRT4 is a matrix protein and becomes cleaved at amino acid 28 after import into mitochondria. Mass spectrometry analysis of proteins that coimmunoprecipitate with SIRT4 identified insulin degrading enzyme and the ADP/ATP carrier proteins, ANT2 and ANT3. SIRT4 exhibits no histone deacetylase activity but functions as an efficient ADP-ribosyltransferase on histones and bovine serum albumin. SIRT4 is expressed in islets of Langerhans and colocalizes with insulin-expressing beta cells. Depletion of SIRT4 from insulin-producing INS-1E cells results in increased insulin secretion in response to glucose. These observations define a new role for mitochondrial SIRT4 in the regulation of insulin secretion.