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A metabolite-derived protein modification integrates glycolysis with KEAP1–NRF2 signalling
Nature ( IF 50.5 ) Pub Date : 2018-10-01 , DOI: 10.1038/s41586-018-0622-0 Michael J Bollong 1 , Gihoon Lee 2, 3 , John S Coukos 2, 3 , Hwayoung Yun 1, 4 , Claudio Zambaldo 1 , Jae Won Chang 2, 3 , Emily N Chin 1 , Insha Ahmad 1 , Arnab K Chatterjee 5 , Luke L Lairson 1, 5 , Peter G Schultz 1, 5 , Raymond E Moellering 2, 3
Nature ( IF 50.5 ) Pub Date : 2018-10-01 , DOI: 10.1038/s41586-018-0622-0 Michael J Bollong 1 , Gihoon Lee 2, 3 , John S Coukos 2, 3 , Hwayoung Yun 1, 4 , Claudio Zambaldo 1 , Jae Won Chang 2, 3 , Emily N Chin 1 , Insha Ahmad 1 , Arnab K Chatterjee 5 , Luke L Lairson 1, 5 , Peter G Schultz 1, 5 , Raymond E Moellering 2, 3
Affiliation
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Mechanisms that integrate the metabolic state of a cell with regulatory pathways are necessary to maintain cellular homeostasis. Endogenous, intrinsically reactive metabolites can form functional, covalent modifications on proteins without the aid of enzymes1,2, and regulate cellular functions such as metabolism3–5 and transcription6. An important ‘sensor’ protein that captures specific metabolic information and transforms it into an appropriate response is KEAP1, which contains reactive cysteine residues that collectively act as an electrophile sensor tuned to respond to reactive species resulting from endogenous and xenobiotic molecules. Covalent modification of KEAP1 results in reduced ubiquitination and the accumulation of NRF27,8, which then initiates the transcription of cytoprotective genes at antioxidant-response element loci. Here we identify a small-molecule inhibitor of the glycolytic enzyme PGK1, and reveal a direct link between glycolysis and NRF2 signalling. Inhibition of PGK1 results in accumulation of the reactive metabolite methylglyoxal, which selectively modifies KEAP1 to form a methylimidazole crosslink between proximal cysteine and arginine residues (MICA). This posttranslational modification results in the dimerization of KEAP1, the accumulation of NRF2 and activation of the NRF2 transcriptional program. These results demonstrate the existence of direct inter-pathway communication between glycolysis and the KEAP1–NRF2 transcriptional axis, provide insight into the metabolic regulation of the cellular stress response, and suggest a therapeutic strategy for controlling the cytoprotective antioxidant response in several human diseases.Inhibition of the glycolytic enzyme PGK1 using a small molecular probe reveals a molecular link between glycolysis and the KEAP1–NRF2 signalling cascade.
中文翻译：
代谢物衍生的蛋白质修饰将糖酵解与 KEAP1–NRF2 信号传导整合在一起
将细胞代谢状态与调节途径整合的机制对于维持细胞稳态是必要的。内源性、内在反应性代谢物可以在不借助酶1,2的情况下对蛋白质形成功能性共价修饰，并调节细胞功能，例如代谢3-5和转录6。KEAP1 是一种重要的“传感器”蛋白，可捕获特定的代谢信息并将其转化为适当的反应，它含有反应性半胱氨酸残基，这些残基共同充当亲电子传感器，调整以响应内源性和外源性分子产生的反应性物质。KEAP1 的共价修饰导致泛素化减少和 NRF27,8 积累，然后在抗氧化反应元件位点启动细胞保护基因的转录。在这里，我们鉴定了糖酵解酶 PGK1 的小分子抑制剂，并揭示了糖酵解和 NRF2 信号传导之间的直接联系。抑制 PGK1 会导致反应性代谢物甲基乙二醛的积累，从而选择性地修饰 KEAP1，在近端半胱氨酸和精氨酸残基 (MICA) 之间形成甲基咪唑交联。这种翻译后修饰导致 KEAP1 的二聚化、NRF2 的积累以及 NRF2 转录程序的激活。这些结果证明了糖酵解和 KEAP1-NRF2 转录轴之间存在直接的通路间通讯，提供了对细胞应激反应的代谢调节的深入了解，并提出了一种在多种人类疾病中控制细胞保护性抗氧化反应的治疗策略。
更新日期：2018-10-01
中文翻译：
代谢物衍生的蛋白质修饰将糖酵解与 KEAP1–NRF2 信号传导整合在一起
将细胞代谢状态与调节途径整合的机制对于维持细胞稳态是必要的。内源性、内在反应性代谢物可以在不借助酶1,2的情况下对蛋白质形成功能性共价修饰，并调节细胞功能，例如代谢3-5和转录6。KEAP1 是一种重要的“传感器”蛋白，可捕获特定的代谢信息并将其转化为适当的反应，它含有反应性半胱氨酸残基，这些残基共同充当亲电子传感器，调整以响应内源性和外源性分子产生的反应性物质。KEAP1 的共价修饰导致泛素化减少和 NRF27,8 积累，然后在抗氧化反应元件位点启动细胞保护基因的转录。在这里，我们鉴定了糖酵解酶 PGK1 的小分子抑制剂，并揭示了糖酵解和 NRF2 信号传导之间的直接联系。抑制 PGK1 会导致反应性代谢物甲基乙二醛的积累，从而选择性地修饰 KEAP1，在近端半胱氨酸和精氨酸残基 (MICA) 之间形成甲基咪唑交联。这种翻译后修饰导致 KEAP1 的二聚化、NRF2 的积累以及 NRF2 转录程序的激活。这些结果证明了糖酵解和 KEAP1-NRF2 转录轴之间存在直接的通路间通讯，提供了对细胞应激反应的代谢调节的深入了解，并提出了一种在多种人类疾病中控制细胞保护性抗氧化反应的治疗策略。
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