A human protein interaction network shows conservation of aging processes between human and invertebrate species.
A human protein interaction network shows conservation of aging processes between human and invertebrate species.
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DOI：
10.1371/journal.pgen.1000414
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发表时间：
2009-03
期刊：
影响因子：
4.5
通讯作者：
Hughes RE
中科院分区：
文献类型：
--
作者：
Bell R;Hubbard A;Chettier R;Chen D;Miller JP;Kapahi P;Tarnopolsky M;Sahasrabuhde S;Melov S;Hughes RE
我们已经绘制了一个蛋白质相互作用网络的人类同源蛋白质，修改无脊椎动物物种的寿命。该网络源自通过无偏高通量酵母双杂交搜索生成的蛋白质组规模的人类蛋白质相互作用核心网络。长寿网络由175种已知通过酵母、线虫或苍蝇功能丧失而增加寿命的蛋白质的人类同源物和2,163种与这些同源物相互作用的其他人类蛋白质组成。总体而言，该网络由2，338个独特蛋白质之间的3，271个二元相互作用组成。人类长寿同源物的平均节点度与核心网络中随机蛋白质组的比较表明，长寿蛋白的人类同源物是高度连接的枢纽，平均节点度为18.8个伙伴。最短路径长度分析表明，该网络中的蛋白质比随机预期的连接更多。为了研究这个网络与人类衰老表型的关系，我们将编码长寿网络蛋白的基因与已知在人类肌肉衰老过程中转录改变的基因进行了比较。在长寿蛋白同源物及其相互作用物的情况下，我们观察到网络中差异表达基因的富集。为了确定人类长寿相互作用蛋白的同源物是否可以调节无脊椎动物的寿命，使用RNAi测试了在人类衰老肌肉中显示显著变化的18种人类FRAP 1相互作用蛋白的同源物对线虫寿命的影响。在测试的18个基因中，33%的基因在秀丽隐杆线虫中被敲低时延长了寿命。这些观察结果表明，在无脊椎动物衰老模型中发现的一类长寿基因与人类衰老有关。他们还表明，长寿蛋白相互作用网络这里提出的是丰富的新的保守的长寿蛋白。对面包酵母、蛔虫和果蝇等模式生物的长寿研究清楚地表明，各种各样的基因突变可以导致寿命延长。事实上，大规模的基因筛选已经确定了数百个基因，当这些基因发生突变，敲除或删除时，将显着提高这些生物体的寿命。尽管在理解模式生物寿命的遗传和基因组决定因素方面取得了很大进展，但无脊椎动物长寿基因与人类衰老和长寿的普遍相关性尚未完全建立。在这项研究中，我们表明，人类同源的无脊椎动物长寿基因的变化，其表达水平在人体组织老化过程中。我们还表明，人类基因编码的蛋白质与人类长寿同源蛋白相互作用，也改变了人类衰老过程中的表达。这些观察结果表明，无脊椎动物寿命遗传控制的广泛模式与人类的衰老和长寿高度相关。我们还提出了一系列可能影响人类寿命的新候选基因和蛋白质。
We have mapped a protein interaction network of human homologs of proteins that modify longevity in invertebrate species. This network is derived from a proteome-scale human protein interaction Core Network generated through unbiased high-throughput yeast two-hybrid searches. The longevity network is composed of 175 human homologs of proteins known to confer increased longevity through loss of function in yeast, nematode, or fly, and 2,163 additional human proteins that interact with these homologs. Overall, the network consists of 3,271 binary interactions among 2,338 unique proteins. A comparison of the average node degree of the human longevity homologs with random sets of proteins in the Core Network indicates that human homologs of longevity proteins are highly connected hubs with a mean node degree of 18.8 partners. Shortest path length analysis shows that proteins in this network are significantly more connected than would be expected by chance. To examine the relationship of this network to human aging phenotypes, we compared the genes encoding longevity network proteins to genes known to be changed transcriptionally during aging in human muscle. In the case of both the longevity protein homologs and their interactors, we observed enrichments for differentially expressed genes in the network. To determine whether homologs of human longevity interacting proteins can modulate life span in invertebrates, homologs of 18 human FRAP1 interacting proteins showing significant changes in human aging muscle were tested for effects on nematode life span using RNAi. Of 18 genes tested, 33% extended life span when knocked-down in Caenorhabditis elegans. These observations indicate that a broad class of longevity genes identified in invertebrate models of aging have relevance to human aging. They also indicate that the longevity protein interaction network presented here is enriched for novel conserved longevity proteins. Studies of longevity in model organisms such as baker's yeast, roundworm, and fruit fly have clearly demonstrated that a diverse array of genetic mutations can result in increased life span. In fact, large-scale genetic screens have identified hundreds of genes that when mutated, knocked down, or deleted will significantly enhance longevity in these organisms. Despite great progress in understanding genetic and genomic determinants of life span in model organisms, the general relevance of invertebrate longevity genes to human aging and longevity has yet to be fully established. In this study, we show that human homologs of invertebrate longevity genes change in their expression levels during aging in human tissue. We also show that human genes encoding proteins that interact with human longevity homolog proteins are also changed in expression during human aging. These observations taken together indicate that the broad patterns underlying genetic control of life span in invertebrates is highly relevant to human aging and longevity. We also present a collection of novel candidate genes and proteins that may influence human life span.
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