Autoregulation of the HAC1 gene is required for sustained activation of the yeast unfolded protein response
Autoregulation of the HAC1 gene is required for sustained activation of the yeast unfolded protein response
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DOI：
10.1111/j.1365-2443.2004.00704.x
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发表时间：
2004-02-01
期刊：
影响因子：
2.1
通讯作者：
Mori, K
中科院分区：
文献类型：
--
作者：
Ogawa, N;Mori, K
真核细胞通过激活称为未折叠蛋白反应（UPR）的转录诱导程序来响应内质网（ER）中未折叠蛋白的积累。酿酒酵母中负责 UPR 的转录因子 Hac1p 受到转录后机制的严格调控。 HAC1 mRNA 必须根据 ER 应激进行剪接以产生 Hac1p，然后通过直接结合其靶基因启动子区域中存在的顺式作用 UPR 元件 (UPRE) 来激活转录。在这里，我们展示了 HAC1 启动子本身响应 ER 应激，诱导其下游基因的转录，与 KAR2 启动子类似； KAR2 基因代表 UPR 的主要靶标。与这一观察结果一致，HAC1 启动子包含一个 UPRE 样序列，该序列对于诱导是必要且充分的，并且 Hac1p 直接与其结合。从缺乏 HAC1 UPRE 的突变型 HAC1 启动子表达 HAC1 基因的细胞无法维持高水平的未剪接或剪接的 HAC1 mRNA，并且在受到损伤数小时后对 ER 应激变得敏感。基于这些结果，我们得出结论，HAC1 基因的自动调节对于 UPR 的持续激活和对 ER 应激的持续抵抗是必需的。
Eukaryotic cells respond to the accumulation of unfolded proteins in the endoplasmic reticulum (ER) by activating a transcriptional induction program termed the unfolded protein response (UPR). The transcription factor Hac1p responsible for the UPR in Saccharomyces cerevisiae is tightly regulated by a post-transcriptional mechanism. HAC1 mRNA must be spliced in response to ER stress to produce Hac1p, which then activates transcription via direct binding to the cis-acting UPR element (UPRE) present in the promoter regions of its target genes. Here, we show that the HAC1 promoter itself responds to ER stress to induce transcription of its downstream gene, similarly to the KAR2 promoter; the KAR2 gene represents a major target of the UPR. Consistent with this observation, the HAC1 promoter contains an UPRE-like sequence, which is necessary and sufficient for the induction and to which Hac1p binds directly. Cells expressing the HAC1 gene from a mutant HAC1 promoter lacking the HAC1 UPRE could not maintain high levels of either unspliced or spliced HAC1 mRNA and became sensitive to ER stress when insulted for hours. Based on these results, we concluded that autoregulation of the HAC1 genes is required for sustained activation of the UPR and sustained resistance to ER stress.