The O-GlcNAc transferase OGT is a conserved and essential regulator of the cellular and organismal response to hypertonic stress.
The O-GlcNAc transferase OGT is a conserved and essential regulator of the cellular and organismal response to hypertonic stress.
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DOI：
10.1371/journal.pgen.1008821
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发表时间：
2020-10
期刊：
影响因子：
4.5
通讯作者：
Lamitina T
中科院分区：
文献类型：
--
作者：
Urso SJ;Comly M;Hanover JA;Lamitina T
保守的O-GlcNAc转移酶OGT O-GlcN酰化细胞内蛋白质的丝氨酸和苏氨酸残基来调节它们的功能。OGT是哺乳动物细胞存活所必需的，但它在细胞生理学中的具体作用却知之甚少。在这里，我们描述了OGT在细胞生理学的一个基本方面的保守要求：高渗应激反应。通过对秀丽线虫的正向遗传筛选，我们发现OGT是渗透保护蛋白表达和适应高渗应激的迫切需要。基因表达分析表明，OGT-1通过转录后机制发挥作用。人类OGT部分挽救了线虫的表型，表明OGT的渗透调节功能是古老的。有趣的是，O-GlcN酰化缺陷形式的人或蠕虫OGT的表达拯救了高渗应激反应表型。然而，缺乏四肽重复(TPR)结构域的OGT蛋白的表达并不能挽救。我们的发现首先证明了OGT在生物体水平上的特定生理作用，并证明了OGT除了在细胞内蛋白质的翻译后O-GlcN酰化中所扮演的角色外，还参与了重要的分子功能。感知和适应环境变化的能力是细胞生命的一个基本特征。环境盐和水浓度的变化会迅速导致细胞体积膨胀或收缩，如果不加以控制，将导致细胞和生物体死亡。所有生物体都制定了类似的维持细胞体积的生理策略。然而，控制这些生理输出的分子机制在动物身上还不是很清楚。在线虫的无偏遗传筛选中，我们发现一种高度保守的酶，称为O-GlcNAc转移酶(OGT)，对于调节对环境溶质水平增加的生理反应是必不可少的。人类形式的OGT可以在功能上取代蠕虫OGT，这表明这种角色在进化过程中是保守的。令人惊讶的是，OGT唯一已知的酶活性并不是这一角色所必需的，这表明这种酶具有重要的未被描述的分子功能。我们的研究揭示了OGT在应对渗透胁迫中的新的动物特异性作用，并表明线虫是一个重要的模型，用于定义响应细胞体积变化的保守分子机制。
The conserved O-GlcNAc transferase OGT O-GlcNAcylates serine and threonine residues of intracellular proteins to regulate their function. OGT is required for viability in mammalian cells, but its specific roles in cellular physiology are poorly understood. Here we describe a conserved requirement for OGT in an essential aspect of cell physiology: the hypertonic stress response. Through a forward genetic screen in Caenorhabditis elegans, we discovered OGT is acutely required for osmoprotective protein expression and adaptation to hypertonic stress. Gene expression analysis shows that ogt-1 functions through a post-transcriptional mechanism. Human OGT partially rescues the C. elegans phenotypes, suggesting that the osmoregulatory functions of OGT are ancient. Intriguingly, expression of O-GlcNAcylation-deficient forms of human or worm OGT rescue the hypertonic stress response phenotype. However, expression of an OGT protein lacking the tetracopeptide repeat (TPR) domain does not rescue. Our findings are among the first to demonstrate a specific physiological role for OGT at the organismal level and demonstrate that OGT engages in important molecular functions outside of its well described roles in post-translational O-GlcNAcylation of intracellular proteins. The ability to sense and adapt to changes in the environment is an essential feature of cellular life. Changes in environmental salt and water concentrations can rapidly cause cell volume swelling or shrinkage and, if left unchecked, will lead to cell and organismal death. All organisms have developed similar physiological strategies for maintaining cell volume. However, the molecular mechanisms that control these physiological outputs are not well understood in animals. Using unbiased genetic screening in C. elegans, we discovered that a highly conserved enzyme called O-GlcNAc transferase (OGT) is essential for regulating physiological responses to increased environmental solute levels. A human form of OGT can functionally substitute for worm OGT, showing that this role is conserved across evolution. Surprisingly, the only known enzymatic activity of OGT was not required for this role, suggesting this enzyme has important undescribed molecular functions. Our studies reveal a new animal-specific role for OGT in the response to osmotic stress and show that C. elegans is an important model for defining the conserved molecular mechanisms that respond to alterations in cell volume.
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影响因子：
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作者：
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作者：
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作者：
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DOI：
10.1073/pnas.0602987103
发表时间：
2006-08-08
影响因子：
11.1
作者：
Lamitina, Todd;Huang, Chunyi George;Strange, Kevin
通讯作者：
Strange, Kevin