Mutation or knock-down of 17β-hydroxysteroid dehydrogenase type 10 cause loss of MRPP1 and impaired processing of mitochondrial heavy strand transcripts
Mutation or knock-down of 17β-hydroxysteroid dehydrogenase type 10 cause loss of MRPP1 and impaired processing of mitochondrial heavy strand transcripts
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DOI：
10.1093/hmg/ddu072
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发表时间：
2014-07-01
影响因子：
3.5
通讯作者：
Zschocke, Johannes
中科院分区：
文献类型：
--
作者：
Deutschmann, Andrea J.;Amberger, Albert;Zschocke, Johannes
β -羟基类固醇脱氢酶10型（HSD10）是由x染色体HSD17B10基因编码的多功能蛋白。该基因突变导致HSD10疾病，其特征是进行性神经异常和心肌病。疾病的进展和症状的严重程度与蛋白质的脱氢酶活性无关。最近，研究表明HSD10是线粒体核糖核酸酶P （RNase P）的重要组成部分，RNase P是线粒体tRNA加工所需的酶，但HSD10在RNase P功能中的作用知之甚少。RNase P由三种不同的蛋白质MRPP1、MRPP2 （HSD10）和MRPP3组成，每一种蛋白质对RNase P的功能都是必不可少的。在这里，我们发现HSD17B10突变p.R130C患者的成纤维细胞中HSD10蛋白水平显著降低。HSD10水平的降低伴随着MRPP1蛋白而非MRPP3蛋白的降低。在HSD10敲除的细胞中，MRPP1蛋白含量也降低，表明HSD10对维持正常MRPP1蛋白水平很重要。HSD10的异位表达部分恢复了HSD10敲除细胞和成纤维细胞中的RNA加工，MRPP1蛋白的表达也恢复到与对照组相当的水平。在患者成纤维细胞和HSD10敲除细胞中，有证据表明，与对照组相比，线粒体重链的前体tRNA转录物的加工受损，但轻链的加工没有受损。我们的研究结果表明，HSD10对RNase P的MRPP1-HSD10亚复合物的维持很重要，HSD10的缺失导致线粒体前体转录加工受损，这可能解释了HSD10疾病中观察到的线粒体功能障碍。
17 beta-Hydroxysteroid dehydrogenase type 10 (HSD10) is multifunctional protein coded by the X-chromosomal HSD17B10 gene. Mutations in this gene cause HSD10 disease characterized by progressive neurological abnormalities and cardiomyopathy. Disease progression and severity of symptoms is unrelated to the protein's dehydrogenase activity. Recently, it was shown that HSD10 is an essential component of mitochondrial Ribonuclease P (RNase P), an enzyme required for mitochondrial tRNA processing, but little is known about the role of HSD10 in RNase P function. RNase P consists of three different proteins MRPP1, MRPP2 (HSD10) and MRPP3, each of which is essential for RNase P function. Here, we show that HSD10 protein levels are significantly reduced in fibroblasts from patients carrying the HSD17B10 mutation p.R130C. A reduction in HSD10 levels was accompanied by a reduction in MRPP1 protein but not MRPP3 protein. In HSD10 knock-down cells, MRPP1 protein content was also reduced, indicating that HSD10 is important for the maintenance of normal MRPP1 protein levels. Ectopic expression of HSD10 partially restored RNA processing in HSD10 knock-down cells and fibroblasts, and also expression of MRPP1 protein was restored to values comparable to controls. In both, patient fibroblasts and HSD10 knock-down cells, there was evidence of impaired processing of precursor tRNA transcripts of the mitochondrial heavy strand but not the light strand compared with controls. Our findings indicate that HSD10 is important for the maintenance of the MRPP1-HSD10 subcomplex of RNase P and that loss of HSD10 causes impaired mitochondrial precursor transcript processing which may explain mitochondrial dysfunction observed in HSD10 disease.