Succinylation of a KEAP1 sensor lysine promotes NRF2 activation.
Succinylation of a KEAP1 sensor lysine promotes NRF2 activation.
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KEAP1 传感器赖氨酸的琥珀酰化可促进 NRF2 激活。
DOI：
10.1101/2023.05.08.539908
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Bollong,MichaelJ
中科院分区：
文献类型：
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作者：
Ibrahim,Lara;Stanton,Caroline;Nutsch,Kayla;Nguyen,Thu;Li-Ma,Chloris;Ko,Yeonjin;Lander,GabrielC;Wiseman,RLuke;Bollong,MichaelJ
代谢和应激反应信号之间的串扰对于维持细胞内稳态是必不可少的。这种串扰通常是通过内源性反应性代谢物对蛋白质的共价修饰来实现的，这些代谢物调节关键的应激反应转录因子，如NRF 2。包括甲基乙二醛、甘油醛3-磷酸、富马酸和衣康酸的代谢产物共价修饰NRF 2阻遏物KEAP 1的传感器半胱氨酸，导致NRF 2的稳定和其细胞保护性转录程序的激活。在这里，我们采用了一种基于shRNA的筛选靶向中央碳代谢酶，以确定额外的调节节点桥接代谢NRF 2激活。通过遗传消耗TCA循环酶琥珀酰辅酶A合成酶或通过直接施用增加的琥珀酸酐导致KEAP 1的赖氨酸131的N-琥珀酰化以激活NRF 2信号传导。这项研究确定KEAP 1能够感应反应性代谢物，不仅由几个半胱氨酸残基，但也由一个保守的赖氨酸残基，表明其有潜力感测反应性代谢信使的扩展库。
Cross talk between metabolism and stress-responsive signaling is essential for maintaining cellular homeostasis. This cross talk is often achieved through covalent modification of proteins by endogenous, reactive metabolites that regulate key stress-responsive transcription factors like NRF2. Metabolites including methylglyoxal, glyceraldehyde 3-phosphate, fumarate, and itaconate covalently modify sensor cysteines of the NRF2 repressor KEAP1, resulting in stabilization of NRF2 and activation of its cytoprotective transcriptional program. Here, we employed a shRNA-based screen targeting the enzymes of central carbon metabolism to identify additional regulatory nodes bridging metabolism to NRF2 activation. Succinic anhydride, increased by genetic depletion of the TCA cycle enzyme succinyl-CoA synthetase or by direct administration, results in N-succinylation of lysine 131 of KEAP1 to activate NRF2 signaling. This study identifies KEAP1 as capable of sensing reactive metabolites not only by several cysteine residues but also by a conserved lysine residue, indicating its potential to sense an expanded repertoire of reactive metabolic messengers.