Identification of a tissue-selective heat shock response regulatory network.
Identification of a tissue-selective heat shock response regulatory network.
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DOI：
10.1371/journal.pgen.1003466
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发表时间：
2013-04
期刊：
影响因子：
4.5
通讯作者：
Morimoto RI
中科院分区：
文献类型：
--
作者：
Guisbert E;Czyz DM;Richter K;McMullen PD;Morimoto RI
热休克反应（HSR）是在急性蛋白毒性应激中生存所必需的，已经在单细胞生物和组织培养细胞中进行了广泛的研究，但在完整的后生动物中进行的研究较少。为了确定秀丽隐杆线虫中控制HSR的调控途径，我们进行了全基因组RNAi筛选，并鉴定了59个基因，这些基因对应于HSR所需的7个阳性激活因子和52个阴性调节因子，它们的敲低导致HSR的组成性激活。这些修饰因子在基因表达、蛋白质合成、蛋白质折叠、运输和蛋白质清除的特定步骤中起作用，并构成后生动物热休克调节网络（HSN）。正调节因子在线虫的所有组织中都起作用，而几乎所有负调节因子都表现出组织选择性作用。蛋白酶体亚基的敲低仅在肠和精膜中强烈诱导HS报告基因表达，而在肌肉细胞中不强烈诱导HS报告基因表达，而TRiC/CCT伴侣蛋白亚基的敲低仅在肌肉细胞中诱导HS报告基因表达。然而，蛋白酶体和TRiC/CCT伴侣蛋白都是普遍表达的，并且是所有组织中清除和折叠所必需的。我们提出，HSN确定了一个关键的蛋白质静止机制子集，该机制根据每个组织的独特功能需求调节HSR。热休克反应（HSR）是一种重要的应激反应，其功能是维持蛋白质折叠稳态或蛋白质稳态，其在人类疾病中的关键作用最近变得明显。以前，我们对高铁的了解大多来自培养的细胞和单细胞生物。在这里，我们提出鉴定秀丽隐杆线虫热休克调控网络（HSN），一个完整的，多细胞生物，使用全基因组RNAi筛选。我们确定了59个HSR的阳性和阴性调节因子，所有这些因子都在蛋白质停滞中具有先前确定的作用，将HSR的功能与其调节联系起来。一些HSN基因以前在其他系统中建立，许多与HSR间接相关，其他是新的。出乎意料的是，几乎所有HSR的负调节因子都以不同的组织选择性模式起作用，尽管它们的广泛表达和普遍的细胞需求。因此，我们的数据表明，HSN由蛋白质平衡机制的一个特定子集组成，该机制以组织选择性的方式将蛋白质平衡网络与HSR调节联系起来。
The heat shock response (HSR) is essential to survive acute proteotoxic stress and has been studied extensively in unicellular organisms and tissue culture cells, but to a lesser extent in intact metazoan animals. To identify the regulatory pathways that control the HSR in Caenorhabditis elegans, we performed a genome-wide RNAi screen and identified 59 genes corresponding to 7 positive activators required for the HSR and 52 negative regulators whose knockdown leads to constitutive activation of the HSR. These modifiers function in specific steps of gene expression, protein synthesis, protein folding, trafficking, and protein clearance, and comprise the metazoan heat shock regulatory network (HSN). Whereas the positive regulators function in all tissues of C. elegans, nearly all of the negative regulators exhibited tissue-selective effects. Knockdown of the subunits of the proteasome strongly induces HS reporter expression only in the intestine and spermatheca but not in muscle cells, while knockdown of subunits of the TRiC/CCT chaperonin induces HS reporter expression only in muscle cells. Yet, both the proteasome and TRiC/CCT chaperonin are ubiquitously expressed and are required for clearance and folding in all tissues. We propose that the HSN identifies a key subset of the proteostasis machinery that regulates the HSR according to the unique functional requirements of each tissue. The heat shock response (HSR) is an essential stress response that functions to maintain protein folding homeostasis, or proteostasis, and whose critical role in human diseases is recently becoming apparent. Previously, most of our understanding of the HSR has come from cultured cells and unicellular organisms. Here we present the identification of the heat shock regulatory network (HSN) in Caenorhabditis elegans, an intact, multicellular organism, using genome-wide RNAi screening. We identify 59 positive and negative regulators of the HSR, all of which have a previously established role in proteostasis, linking the function of the HSR to its regulation. Some HSN genes were previously established in other systems, many were indirectly linked to HSR, and others are novel. Unexpectedly, almost all negative regulators of the HSR act in distinct, tissue-selective patterns, despite their broad expression and universal cellular requirements. Therefore, our data indicate that the HSN consists of a specific subset of the proteostasis machinery that functions to link the proteostasis network to HSR regulation in a tissue-selective manner.
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DOI：
10.1126/science.1166175
发表时间：
2009-01-30
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Anderson LL;Mao X;Scott BA;Crowder CM
通讯作者：
Crowder CM
影响因子：
10.5
作者：
Guisbert, E;Herman, C;Gross, CA
通讯作者：
Gross, CA
影响因子：
3.3
作者：
Elefant, F;Palter, KB
通讯作者：
Palter, KB
影响因子：
64.8
作者：
Calfon, M;Zeng, HQ;Ron, D
通讯作者：
Ron, D
影响因子：
4.5
作者：
Hansen M;Hsu AL;Dillin A;Kenyon C
通讯作者：
Kenyon C