S-lactoyl modification of KEAP1 by a reactive glycolytic metabolite activates NRF2 signaling.
S-lactoyl modification of KEAP1 by a reactive glycolytic metabolite activates NRF2 signaling.
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DOI：
10.1073/pnas.2300763120
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发表时间：
2023-05-16
影响因子：
11.1
通讯作者：
Bollong, Michael J.
中科院分区：
文献类型：
--
作者：
Ko, Yeonjin;Hong, Mannkyu;Lee, Seungbeom;Kumar, Manoj;Ibrahim, Lara;Nutsch, Kayla;Stanton, Caroline;Sandoval, Braddock;Sondermann, Phillip;Bulos, Maya L.;Iaconelli, Jonathan;Chatterjee, Arnab K.;Wiseman, R. Luke;Schultz, Peter G.;Bollong, Michael J.
一些反应性内源性代谢物已被证明激活NRF2驱动的哺乳动物细胞的氧化应激反应。在这里，我们通过展示对糖酵解的最后一步丙酮酸激酶的药物抑制，导致3-磷酸甘油醛的积累，从而导致NRF2抑制蛋白Keap1的共价修饰和失活，从而扩展了这一反应性代谢物的谱系。这项工作确定了半胱氨酸的一种非酶衍生的翻译后修饰，称为S-乳酸化，并进一步建立在现有数据的基础上，糖酵解通过半胱氨酸的反应性代谢物衍生的修饰直接与Keap1-NRF2信号通路联系。Keap1(Kelch-like ECH相关蛋白)是氧化应激反应转录因子红血球相关因子2(NRF2)的细胞质阻遏因子，它通过修饰其半胱氨酸残基来感知亲电剂的存在。除了外源化合物，几种反应性代谢物已经被证明可以共价修饰Keap1上的关键半胱氨酸，尽管这些分子的完整谱系及其各自的修饰仍未确定。在这里，我们报告了sAKZ692的发现，这是一种通过高通量筛选确定的小分子，通过抑制糖酵解酶丙酮酸激酶来刺激细胞中NRF2的转录活性。SAKZ692处理促进代谢产物3-磷酸甘油醛的积聚，该代谢产物导致KEAP1半胱氨酸感受器残基的S-乳酸修饰，导致NRF2依赖的转录。这项工作确定了来自活性中心碳代谢物的半胱氨酸的翻译后修饰，并有助于进一步确定代谢和细胞氧化应激传感机制之间的复杂关系。
Several reactive endogenous metabolites have been shown to activate the NRF2-driven oxidative stress response in mammalian cells. Here, we expand this repertoire of reactive metabolites by showing that pharmacological inhibition of pyruvate kinase, the last step in glycolysis, results in the accumulation of glyceraldehyde 3-phosphate, a metabolite that results in the covalent modification and inactivation of the NRF2 repressor protein KEAP1. This work identifies a nonenzymatically derived posttranslational modification of cysteine, termed S-lactoylation, and further builds upon existing data that glycolysis directly communicates to the KEAP1–NRF2 signaling pathway through reactive metabolite-derived modifications of cysteine. KEAP1 (Kelch-like ECH-associated protein), a cytoplasmic repressor of the oxidative stress responsive transcription factor Nuclear factor erythroid 2-related factor 2 (NRF2), senses the presence of electrophilic agents by modification of its sensor cysteine residues. In addition to xenobiotics, several reactive metabolites have been shown to covalently modify key cysteines on KEAP1, although the full repertoire of these molecules and their respective modifications remain undefined. Here, we report the discovery of sAKZ692, a small molecule identified by high-throughput screening that stimulates NRF2 transcriptional activity in cells by inhibiting the glycolytic enzyme pyruvate kinase. sAKZ692 treatment promotes the buildup of glyceraldehyde 3-phosphate, a metabolite which leads to S-lactate modification of cysteine sensor residues of KEAP1, resulting in NRF2-dependent transcription. This work identifies a posttranslational modification of cysteine derived from a reactive central carbon metabolite and helps further define the complex relationship between metabolism and the oxidative stress-sensing machinery of the cell.
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DOI：
10.3390/antiox9101025
发表时间：
2020-10-21
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
--
作者：
Ibrahim L;Mesgarzadeh J;Xu I;Powers ET;Wiseman RL;Bollong MJ
通讯作者：
Bollong MJ
影响因子：
14.9
作者：
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通讯作者：
Biswal S
DOI：
10.1126/science.1211485
发表时间：
2011-12-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Anastasiou D;Poulogiannis G;Asara JM;Boxer MB;Jiang JK;Shen M;Bellinger G;Sasaki AT;Locasale JW;Auld DS;Thomas CJ;Vander Heiden MG;Cantley LC
通讯作者：
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影响因子：
50.3
作者：
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通讯作者：
Furge, Kyle A.
影响因子：
8.6
作者：
Gaffney, Dominique O.;Jennings, Erin Q.;Galligan, James J.
通讯作者：
Galligan, James J.