Glycosylation of KEAP1 links nutrient sensing to redox stress signaling
Glycosylation of KEAP1 links nutrient sensing to redox stress signaling
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DOI：
10.15252/embj.201696113
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发表时间：
2017-08-01
期刊：
影响因子：
11.4
通讯作者：
Chi, Jen-Tsan
中科院分区：
文献类型：
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作者：
Chen, Po-Han;Smith, Timothy J.;Chi, Jen-Tsan
O-GlcNAc酰化是一种重要的营养敏感性翻译后修饰，但其生物化学和表型效应仍不完全清楚。为了解决这个问题，我们研究了全局转录响应O-GlcNAc化扰动。出乎意料的是，O-GlcNAc转移酶（OGT）抑制的许多转录效应是由于氧化还原应激耐受性的主要调节因子NRF 2的激活。此外，我们发现低OGT活性的特征与多个肿瘤表达数据集中的NRF 2活化强烈相关。在这些信息的指导下，我们确定了KEAP 1（也称为KLHL 19），NRF 2的主要负调节因子，作为OGT的直接底物。我们表明，O-GlcNAc酰化KEAP 1在丝氨酸104是必需的有效的泛素化和降解的NRF 2。有趣的是，O-GlcNAc水平和NRF 2活化响应于葡萄糖波动而共同变化，表明KEAP 1 O-GlcNAc化将营养感测与下游胁迫抗性联系起来。我们的研究结果揭示了营养敏感性糖基化和NRF 2信号之间的一种新的调控联系，并为未来在各种实验和疾病背景下发现其他KLHL家族蛋白功能重要的O-GlcNAc化事件的方法提供了蓝图。
O-GlcNAcylation is an essential, nutrient-sensitive post-translational modification, but its biochemical and phenotypic effects remain incompletely understood. To address this question, we investigated the global transcriptional response to perturbations in O-GlcNAcylation. Unexpectedly, many transcriptional effects of O-GlcNAc transferase (OGT) inhibition were due to the activation of NRF2, the master regulator of redox stress tolerance. Moreover, we found that a signature of low OGT activity strongly correlates with NRF2 activation in multiple tumor expression datasets. Guided by this information, we identified KEAP1 (also known as KLHL19), the primary negative regulator of NRF2, as a direct substrate of OGT. We show that O-GlcNAcylation of KEAP1 at serine 104 is required for the efficient ubiquitination and degradation of NRF2. Interestingly, O-GlcNAc levels and NRF2 activation co-vary in response to glucose fluctuations, indicating that KEAP1 O-GlcNAcylation links nutrient sensing to downstream stress resistance. Our results reveal a novel regulatory connection between nutrient-sensitive glycosylation and NRF2 signaling and provide a blueprint for future approaches to discover functionally important O-GlcNAcylation events on other KLHL family proteins in various experimental and disease contexts.