LRPPRC and SLIRP interact in a ribonucleoprotein complex that regulates posttranscriptional gene expression in mitochondria.
LRPPRC and SLIRP interact in a ribonucleoprotein complex that regulates posttranscriptional gene expression in mitochondria.
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DOI：
10.1091/mbc.e10-01-0047
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发表时间：
2010-04-15
影响因子：
3.3
通讯作者：
LSFC Consortium
中科院分区：
文献类型：
--
作者：
Sasarman F;Brunel-Guitton C;Antonicka H;Wai T;Shoubridge EA;LSFC Consortium
PPR家族蛋白LRPPRC与Leigh综合征（一种致命的神经退行性疾病）的法裔加拿大变体有关。LRPPRC作为RNP与SLIRP（茎环RNA结合蛋白）复合物的一部分，在线粒体转录后基因表达中发挥作用，以调节成熟mRNA的稳定性和处理。LRPPRC的突变是Leigh综合征（LSFC）的法裔加拿大变体的原因，LSFC是一种由细胞色素c氧化酶（考克斯）的组织特异性缺陷引起的神经退行性疾病。为了探讨疾病的发病机制，我们研究了LRPPRC在LSFC和对照成纤维细胞中的功能。LSFC细胞中突变的LRPPRC的水平降低，这导致大多数线粒体mRNA的稳态水平降低，但不是rRNA或tRNA，这是一种可以通过siRNA介导的LRPPRC敲低在对照细胞中再现的表型。原始记录的处理似乎正常。LSFC细胞中线粒体蛋白质合成的缺陷不成比例地影响考克斯亚基，导致孤立的考克斯组装缺陷。LRPPRC的进一步敲低在所有含有mtDNA编码的亚基的氧化磷酸化复合物中产生普遍的组装缺陷，这是由于所有线粒体mRNA的严重减少。LRPPRC以高分子量复合物的形式存在，并与茎环RNA结合蛋白SLIRP共免疫沉淀。虽然这种相互作用不依赖于线粒体mRNA，但这两种蛋白质在其缺失下显示出降低的稳定性。这些结果暗示LRPPRC在转录后线粒体基因表达中作为核糖核蛋白复合物的一部分调节成熟mRNA的稳定性和处理。
The PPR family protein LRPPRC is implicated in the French Canadian variant of Leigh syndrome, a fatal neurodegenerative disease. LRPPRC functions in posttranscriptional mitochondrial gene expression as part of an RNP complex with SLIRP, a stem-loop RNA-binding protein, to regulate the stability and handling of mature mRNAs. Mutations in LRPPRC are responsible for the French Canadian variant of Leigh syndrome (LSFC), a neurodegenerative disorder caused by a tissue-specific deficiency in cytochrome c oxidase (COX). To investigate the pathogenic mechanism of disease, we studied LRPPRC function in LSFC and control fibroblasts. The level of mutated LRPPRC is reduced in LSFC cells, and this results in decreased steady-state levels of most mitochondrial mRNAs, but not rRNAs or tRNAs, a phenotype that can be reproduced by siRNA-mediated knockdown of LRPPRC in control cells. Processing of the primary transcripts appears normal. The resultant defect in mitochondrial protein synthesis in LSFC cells disproportionately affects the COX subunits, leading to an isolated COX assembly defect. Further knockdown of LRPPRC produces a generalized assembly defect in all oxidative phosphorylation complexes containing mtDNA-encoded subunits, due to a severe decrease in all mitochondrial mRNAs. LRPPRC exists in a high-molecular-weight complex, and it coimmunoprecipitates with SLIRP, a stem-loop RNA-binding protein. Although this interaction does not depend on mitochondrial mRNA, both proteins show reduced stability in its absence. These results implicate LRPPRC in posttranscriptional mitochondrial gene expression as part of a ribonucleoprotein complex that regulates the stability and handling of mature mRNAs.
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影响因子：
11.4
作者：
Topisirovic, Ivan;Siddiqui, Nadeem;Borden, Katherine L. B.
通讯作者：
Borden, Katherine L. B.
影响因子：
64.8
作者：
MONTOYA, J;OJALA, D;ATTARDI, G
通讯作者：
ATTARDI, G
影响因子：
3.5
作者：
Davies, Stefan M. K.;Rackham, Oliver;Filipovska, Aleksandra
通讯作者：
Filipovska, Aleksandra
影响因子：
4.5
作者：
Baughman JM;Nilsson R;Gohil VM;Arlow DH;Gauhar Z;Mootha VK
通讯作者：
Mootha VK
DOI：
10.1007/978-1-59745-521-3_10
发表时间：
2009-01-01
期刊：
MITOCHONDRIAL DNA: METHODS AND PROTOCOLS
影响因子：
--
作者：
Leary, Scot C.;Sasarman, Florin
通讯作者：
Sasarman, Florin