Genetic interactions due to constitutive and inducible gene regulation mediated by the unfolded protein response in C. elegans.
Genetic interactions due to constitutive and inducible gene regulation mediated by the unfolded protein response in C. elegans.
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DOI：
10.1371/journal.pgen.0010037
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发表时间：
2005-09
期刊：
影响因子：
4.5
通讯作者：
Kaufman RJ
中科院分区：
文献类型：
--
作者：
Shen X;Ellis RE;Sakaki K;Kaufman RJ
未折叠蛋白反应(UPR)是一种适应性信号通路，用于感知和缓解内质网(ER)中蛋白质折叠的压力。在哺乳动物中，UPR是通过三个近端传感器PERK/PEK、IRE1和ATF6介导的。PERK/PEK是一种蛋白激酶，能使真核细胞翻译起始因子2的α亚基磷酸化，从而抑制蛋白质合成。IRE1的激活诱导XBP1mRNA的剪接产生一种有效的转录因子。ATF6是一种跨膜转录因子，在内质网应激时被裂解激活。我们发现，在线虫中，缺失IRE-1或XBP-1之一是合成致死的，缺失ATF-6或PEK-1都会导致幼虫阶段2的发育停滞。因此，在线虫中，ATF-6与Pek-1协同作用，补充IRE-1和XBP-1的发育需求。微阵列分析鉴定了诱导型UPR(i-UPR)基因，以及大量在正常发育过程中需要内质网应力转导的组成型UPR(c-UPR)基因。虽然IRE-1和XBP-1共同调控大多数I-UPR基因的转录，但它们都是表达不重叠的c-UPR基因所必需的，这表明它们具有不同的功能。有趣的是，线虫ATF-6在内质网应激后调节少数I-UPR基因，但许多c-UPR基因的表达是必需的，这表明它在发育和动态平衡中的重要性。相比之下，大约23%的i-UPR基因的诱导需要Pek-1，但对于c-UPR来说，Pek-1是必不可少的。由于Pek-1和ATF-6主要通过一组不同于IRE-1和XBP-1的非重叠靶点发挥作用，因此至少需要两种协调反应来通过不同的机制缓解内质网应激。最后，我们的阵列研究确定了肝脏特异性转录因子CREBh是一个在后生动物进化过程中保守的新的UPR基因。内质网(ER)是细胞内的细胞器，蛋白质在转运到细胞表面之前在这里折叠和组装。ER包含一个微调的质量控制装置，以确保不正确折叠的蛋白质保留在ER管腔中。各种生理需求、环境扰动和病理条件都会损害内质网中的蛋白质折叠，导致未折叠蛋白质的积累。未折叠蛋白应答(UPR)是一种进化保守的细胞内适应性信号通路，可减轻内质网中蛋白质折叠缺陷。未折叠的蛋白质信号通过ATF-6、PEK-1和IRE-1/XBP-1三条途径从内质网传递到细胞核。然而，目前尚不清楚这三条通路如何协调下游转录激活来调节细胞适应或细胞死亡。作者以线虫秀丽线虫为研究对象，对这三条UPR途径进行了全面的遗传和基因表达分析。研究结果表明，在存在和不存在内质网应激的情况下，UPR以一种比之前所知的更复杂和多样化的方式调控数百个基因的表达。
The unfolded protein response (UPR) is an adaptive signaling pathway utilized to sense and alleviate the stress of protein folding in the endoplasmic reticulum (ER). In mammals, the UPR is mediated through three proximal sensors PERK/PEK, IRE1, and ATF6. PERK/PEK is a protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 to inhibit protein synthesis. Activation of IRE1 induces splicing of XBP1 mRNA to produce a potent transcription factor. ATF6 is a transmembrane transcription factor that is activated by cleavage upon ER stress. We show that in Caenorhabditis elegans, deletion of either ire-1 or xbp-1 is synthetically lethal with deletion of either atf-6 or pek-1, both producing a developmental arrest at larval stage 2. Therefore, in C. elegans, atf-6 acts synergistically with pek-1 to complement the developmental requirement for ire-1 and xbp-1. Microarray analysis identified inducible UPR (i-UPR) genes, as well as numerous constitutive UPR (c-UPR) genes that require the ER stress transducers during normal development. Although ire-1 and xbp-1 together regulate transcription of most i-UPR genes, they are each required for expression of nonoverlapping sets of c-UPR genes, suggesting that they have distinct functions. Intriguingly, C. elegans atf-6 regulates few i-UPR genes following ER stress, but is required for the expression of many c-UPR genes, indicating its importance during development and homeostasis. In contrast, pek-1 is required for induction of approximately 23% of i-UPR genes but is dispensable for the c-UPR. As pek-1 and atf-6 mainly act through sets of nonoverlapping targets that are different from ire-1 and xbp-1 targets, at least two coordinated responses are required to alleviate ER stress by distinct mechanisms. Finally, our array study identified the liver-specific transcription factor CREBh as a novel UPR gene conserved during metazoan evolution. The endoplasmic reticulum (ER) is an intracellular organelle where proteins fold and assemble prior to transport to the cell surface. The ER contains a finely tuned quality control apparatus to ensure that improperly folded proteins are retained in the ER lumen. A variety of physiological demands, environmental perturbations, and pathological conditions compromise protein folding in the ER and lead to the accumulation of unfolded proteins. The unfolded protein response (UPR) is an evolutionarily conserved intracellular adaptive signaling pathway that alleviates protein-folding defects in the ER. The unfolded protein signal is transmitted from the ER to the nucleus by three pathways involving the proteins ATF-6, PEK-1, and IRE-1/XBP-1. However, it is not known how these three pathways coordinate downstream transcriptional activation to mediate either cell adaptation or cell death. The authors have studied the nematode Caenorhabditis elegans to present a comprehensive genetic and gene expression analysis of the three UPR pathways. The findings demonstrate that the UPR regulates the expression of hundreds of genes in the presence, as well as the absence, of ER stress in a manner that is more complex and diverse than previously known.
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影响因子：
3.3
作者：
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通讯作者：
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哺乳动物转录因子 ATF6 以跨膜蛋白的形式合成，并在内质网应激时通过蛋白水解激活
影响因子：
3.3
作者：
Haze, K;Yoshida, H;Mori, K
通讯作者：
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影响因子：
21.3
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