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首页> 外文期刊>Molecular and Cellular Biology >Activity of the Yap1 Transcription Factor in Saccharomyces cerevisiae Is Modulated by Methylglyoxal, a Metabolite Derived from Glycolysis
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Activity of the Yap1 Transcription Factor in Saccharomyces cerevisiae Is Modulated by Methylglyoxal, a Metabolite Derived from Glycolysis

机译：酿酒酵母中Yap1转录因子的活性是由甲基乙二醛（糖酵解衍生的代谢产物）调节的。

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Methylglyoxal (MG) is synthesized during glycolysis, although it inhibits cell growth in all types of organisms. Hence, it has long been asked why such a toxic metabolite is synthesized in vivo. Glyoxalase I is a major enzyme detoxifying MG. Here we show that the Yap1 transcription factor, which is critical for the oxidative-stress response in Saccharomyces cerevisiae, is constitutively concentrated in the nucleus and activates the expression of its target genes in a glyoxalase I-deficient mutant. Yap1 contains six cysteine residues in two cysteine-rich domains (CRDs), i.e., three cysteine residues clustering near the N terminus (n-CRD) and the remaining three cysteine residues near the C terminus (c-CRD). We reveal that any of the three cysteine residues in the c-CRD is sufficient for MG to allow Yap1 to translocate into the nucleus and to activate the expression of its target gene. A Yap1 mutant possessing only one cysteine residue in the c-CRD but no cysteine in the n-CRD and deletion of the basic leucine zipper domain can concentrate in the nucleus with MG treatment. However, substitution of all the cysteine residues in Yap1 abolishes the ability of this transcription factor to concentrate in the nucleus following MG treatment. The redox status of Yap1 is substantially unchanged, and protein(s) interaction with Yap1 through disulfide bond is hardly detected in cells treated with MG. Collectively, neither intermolecular nor intramolecular disulfide bond formation seems to be involved in Yap1 activation by MG. Moreover, we show that nucleocytoplasmic localization of Yap1 closely correlates with growth phase and intracellular MG level. We propose a novel regulatory pathway underlying Yap1 activation by a natural metabolite in the cell.
机译：甲基乙二醛（MG）是在糖酵解过程中合成的，尽管它抑制所有类型生物中的细胞生长。因此，长期以来人们一直问为什么在体内合成这种有毒代谢产物。乙二醛酶I是一种主要的解毒MG酶。在这里，我们显示Yap1转录因子在啤酒酵母（Saccharomyces cerevisiae）中的氧化应激反应至关重要，它主要集中在细胞核中，并激活乙二醛酶I缺陷型突变体中其靶基因的表达。 。 Yap1在两个富含半胱氨酸的域（CRD）中包含六个半胱氨酸残基，即在N末端（n-CRD）附近聚集的三个半胱氨酸残基，在C末端（c-CRD）附近的其余三个半胱氨酸残基。我们揭示c-CRD中的三个半胱氨酸残基中的任何一个都足以使MG允许Yap1易位到细胞核中并激活其靶基因的表达。 Yap1突变体仅在c-CRD中具有一个半胱氨酸残基，而在n-CRD中不具有半胱氨酸，并且碱性亮氨酸拉链结构域的缺失可以通过MG处理集中在细胞核中。然而，Yap1中所有半胱氨酸残基的取代消除了该转录因子在MG治疗后集中于细胞核的能力。 Yap1的氧化还原状态基本不变，并且在用MG处理的细胞中几乎未检测到蛋白质通过二硫键与Yap1的相互作用。总的来说，分子间或分子内二硫键的形成似乎都不参与MG的Yap1激活。此外，我们表明Yap1的核质定位与生长阶段和细胞内MG水平密切相关。我们提出了一种由细胞中的天然代谢产物激活Yap1的新型调控途径。

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