Rab34 and its effector munc13-2 constitute a new pathway modulating protein secretion in the cellular response to hyperglycemia
Rab34 and its effector munc13-2 constitute a new pathway modulating protein secretion in the cellular response to hyperglycemia
复制标题
DOI：
10.1152/ajpcell.00286.2009
复制
发表时间：
2009-10-01
影响因子：
5.5
通讯作者：
Silverman, Mel
中科院分区：
文献类型：
--
作者：
Goldenberg, Neil M.;Silverman, Mel
Goldenberg NM，Silverman M. Rab 34及其效应子munc 13 -2构成了调节细胞对高血糖反应的蛋白分泌的新途径。美国生理学杂志细胞生理学297：C1053-C1058，2009年。首次发表于2009年7月29日; doi：10.1152/ajpcell.00286.2009。糖尿病肾病（DN）是西方世界需要透析的终末期肾病的主要原因。临床研究表明，严格控制血糖水平可以降低大多数糖尿病并发症的风险，这强调了了解细胞对高血糖反应的重要性。我们的工作确定了一个新的途径，在这种反应的潜在意义，连接高血糖刺激的组成性蛋白分泌通过一个途径，涉及munc 13和rab 34。这两种蛋白质先前已被证明通过munc 13同源结构域2（MHD 2）在高尔基体相互作用。在本研究中，使用培养的大鼠肾小球系膜细胞（RMC），我们发现，高葡萄糖诱导的内源性munc 13 -2的上调增加了模型蛋白，水泡性口炎病毒糖蛋白-绿色荧光蛋白（VSVG-GFP）的分泌，而小干扰（si）RNA介导的munc 13 -2或rab 34的敲低废除了这种效果。类似地，在用野生型munc 13 -2转染HeLa细胞后观察到VSVG-GFP分泌增加，但当用缺失MHD 2结构域的突变蛋白转染HeLa细胞时则没有。最后，我们发现高糖刺激的RMC中纤连蛋白的分泌被munc 13 -2的siRNA敲低所消除。总的来说，我们的研究结果表明，我们观察到的高葡萄糖诱导的蛋白分泌的机制基础是通过munc 13和rab 34的相互作用，这表明一个潜在的关键作用，这个新描述的途径在DN的发病机制。
Goldenberg NM, Silverman M. Rab34 and its effector munc13-2 constitute a new pathway modulating protein secretion in the cellular response to hyperglycemia. Am J Physiol Cell Physiol 297: C1053-C1058, 2009. First published July 29, 2009; doi: 10.1152/ajpcell.00286.2009.-Diabetic nephropathy (DN) is the leading cause of end-stage renal disease requiring dialysis in the Western world. Clinical studies reveal that stringent control of blood glucose levels reduces the risk of most diabetic complications, underscoring the importance of understanding the cellular response to hyperglycemia. Our work identifies a new pathway of potential significance in this response, linking hyperglycemia to the stimulation of constitutive protein secretion via a pathway involving munc13 and rab34. These two proteins have previously been shown to interact at the Golgi via the munc13 homology domain 2 (MHD2). In the present study, using cultured rat mesangial cells (RMC), we show that high glucose-induced upregulation of endogenous munc13-2 increases secretion of the model protein, vesicular stomatitis virus glycoprotein-green fluorescent protein (VSVG-GFP), while small interfering (si) RNA-mediated knockdown of either munc13-2 or rab34 abolishes this effect. Similarly, increased secretion of VSVG-GFP is observed following transfection of HeLa cells with wild-type munc13-2, but not when HeLa cells are transfected with a mutant protein in which the MHD2 domain is deleted. Finally, we show that high glucose-stimulated secretion of fibronectin in RMC is abolished by siRNA knockdown of munc13-2. Collectively, our results demonstrate that the mechanistic basis for our observed high glucose-induced protein secretion is through interaction of munc13 and rab34, indicating a potentially critical role for this newly described pathway in the pathogenesis of DN.