Pan-Cancer Analysis of Mitochondria Chaperone-Client Co-Expression Reveals Chaperone Functional Partitioning
Pan-Cancer Analysis of Mitochondria Chaperone-Client Co-Expression Reveals Chaperone Functional Partitioning
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DOI：
10.3390/cancers12040825
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发表时间：
2020-04-01
期刊：
影响因子：
5.2
通讯作者：
Rotblat, Barak
中科院分区：
文献类型：
--
作者：
Galai, Geut;Ben-David, Hila;Rotblat, Barak
新陈代谢重新编程是癌症的一个标志。这种重新编程需要上调特定线粒体蛋白质的表达，从而增加了线粒体蛋白质质量控制的负担。然而，人们对线粒体伴侣与其客户之间相互作用的特异性以及线粒体伴侣与客户共表达的协调程度知之甚少。我们假设，线粒体中的伴侣与其客户之间的物理相互作用应该表现在两个转录本的共同表达模式中。利用肿瘤基因组图谱(TCGA)中13个肿瘤实体的基因表达数据，构建了线粒体伴侣-客户共表达网络。我们确定该网络由三个不同的模块组成，每个模块都填充了属于不同功能组的独特的伴侣-客户共表达对。令人惊讶的是，已知组成功能复合体的伴侣蛋白HSPD1和HSPE1各自占据了不同的模块：HSPD1与三羧酸循环循环酶共表达，而HSPE1与参与氧化磷酸化的蛋白质共表达。重要的是，我们发现每个模块中的基因都富含离散的转录因子结合位点，这表明了协同共表达的机制。我们认为，我们的线粒体伴侣-客户相互作用组可以帮助识别支持特定线粒体途径的伴侣，并提出代谢适应的基本原理。
Metabolic reprogramming is a hallmark of cancer. Such reprogramming entails the up-regulation of the expression of specific mitochondrial proteins, thus increasing the burden on the mitochondrial protein quality control. However, very little is known about the specificity of interactions between mitochondrial chaperones and their clients, or to what extent the mitochondrial chaperone-client co-expression is coordinated. We hypothesized that a physical interaction between a chaperone and its client in mitochondria ought to be manifested in the co-expression pattern of both transcripts. Using The Cancer Genome Atlas (TCGA) gene expression data from 13 tumor entities, we constructed the mitochondrial chaperone-client co-expression network. We determined that the network is comprised of three distinct modules, each populated with unique chaperone-clients co-expression pairs belonging to distinct functional groups. Surprisingly, chaperonins HSPD1 and HSPE1, which are known to comprise a functional complex, each occupied a different module: HSPD1 co-expressed with tricarboxylic acid cycle cycle enzymes, while HSPE1 co-expressed with proteins involved in oxidative phosphorylation. Importantly, we found that the genes in each module were enriched for discrete transcription factor binding sites, suggesting the mechanism for the coordinated co-expression. We propose that our mitochondrial chaperone-client interactome can facilitate the identification of chaperones supporting specific mitochondrial pathways and bring forth a fundamental principle in metabolic adaptation.