Keap1翻译后修饰调控氧化应激相关疾病

doi:10.16352/j.issn.1001-6325.2025.01.0107

基础医学与临床 ›› 2025, Vol. 45 ›› Issue (1): 107-111.doi: 10.16352/j.issn.1001-6325.2025.01.0107

Keap1翻译后修饰调控氧化应激相关疾病

瞿瑛¹, 毛彩云², 钟晴², 张蓉², 宋运佳^2*

黑龙江中医药大学 1.2022级药理学专业; 2.基础医学院药理教研组,黑龙江哈尔滨 150040

收稿日期:2024-04-19 修回日期:2024-07-05 出版日期:2025-01-05 发布日期:2024-12-25
通讯作者: ^*songyunjia666@126.com
基金资助:
国家自然科学基金(82204792);中国博士后科学基金(2002M711089)

Post-translational modification of Keap1 regulates oxidative stress-related diseases

QU Ying¹, MAO Caiyun², ZHONG Qing², ZHANG Rong², SONG Yunjia^2*

1. Pharmacology, Grade 2022; 2. Department of Pharmacology, School of Basic Medicine, Heilongjiang University of Chinese Medicine, Harbin 150040, China

Received:2024-04-19 Revised:2024-07-05 Online:2025-01-05 Published:2024-12-25
Contact: ^*songyunjia666@126.com

摘要/Abstract

摘要： Keap1-Nrf2信号通路的激活是细胞对抗氧化应激的重要机制。氧化应激条件下,Keap1受到谷胱甘肽化、烷基化以及S-巯基化等翻译后修饰(PTM)的影响,与Nrf2的结合被减弱,导致Nrf2积累、核易位以及下游解毒和抗氧化防御蛋白质的表达和转录。Keap1的PTM参与调控癌、帕金森病和动脉粥样硬化等多种氧化应激相关疾病,例如烷基化抑制腹主动脉瘤形成、甲基化促进乳腺癌固有抵抗以及S-巯基化改善动脉粥样硬化,为寻找新的药物靶点和生物标志物提供理论基础。

关键词: Keap1, 氧化应激, 翻译后修饰, 作用机制

Abstract: The activation of Keap1-Nrf2 signaling pathway is an important mechanism for cells to resist oxidative stress. Under oxidative stress, Keap1 is affected by post-translational modification(PTM) such as glutathione, alkylation and S-sulfhydrylation, which weakens its binding to Nrf2, leading to Nrf2 accumulation, nuclear translocation and the expression and transcription of downstream detoxification and antioxidant defense proteins. The PTM of Keap1 is involved in the regulation of a variety of oxidative stress-related diseases such as cancer, Parkinson′s disease and atherosclerosis. For example, alkylation inhibits abdominal aortic aneurysm formation, methylation promotes innate resistance of breast cancer, and S-sulfhydrylation improves atherosclerosis, which provides a theoretical basis for finding new drug targets and biomarkers.

Key words: Keap1, oxidative stress, post-translational modifications, mechanism of action

中图分类号:

R966

瞿瑛, 毛彩云, 钟晴, 张蓉, 宋运佳. Keap1翻译后修饰调控氧化应激相关疾病[J]. 基础医学与临床, 2025, 45(1): 107-111.

QU Ying, MAO Caiyun, ZHONG Qing, ZHANG Rong, SONG Yunjia. Post-translational modification of Keap1 regulates oxidative stress-related diseases[J]. Basic & Clinical Medicine, 2025, 45(1): 107-111.

参考文献

[1] Ibrahim L, Stanton C, Nutsch K, et al. Succinylation of a KEAP1 sensor lysine promotes NRF2 activation[J]. Cell Chem Biol, 2023, 30: 1295-1302.
[2] Selvan GT, Ashok AK, Rao SJA, et al. Nrf2-regulated antioxidant response ameliorating ionizing radiation-induced damages explored through in vitro and molecular dynamics simulations[J]. J Biomol Struct Dyn, 2023, 41: 8472-8484.
[3] Ulasov AV, Rosenkranz AA, Georgiev GP, et al. Nrf2/Keap1/ARE signaling: towards specific regulation[J]. Life Sci, 2022, 291: 120111.doi:10.1016/j.lfs.2021.120111
[4] Murphy MP, Bayir H, Belousov V, et al. Guidelines for measuring reactive oxygen species and oxidative damage in cells and in vivo[J]. Nat Metab, 2022, 4: 651-662.
[5] Suzuki T, Takahashi J, Yamamoto M. Molecular Basis of the KEAP1-NRF2 Signaling Pathway[J]. Mol Cells, 2023, 46: 133-141.
[6] Li N, Wang J, Zang X, et al. H(2)S probe CPC inhibits autophagy and promotes apoptosis by inhibiting glutathionylation of Keap1 at Cys434[J]. Apoptosis, 2021, 26: 111-131.
[7] Gambhir L, Checker R, Thoh M, et al. 1,4-Naphthoquinone, a pro-oxidant, suppresses immune responses via KEAP-1 glutathionylation[J]. Biochem Pharmacol, 2014, 88: 95-105.
[8] Wang L, Qu G, Gao Y, et al. A small molecule targeting glutathione activates Nrf2 and inhibits cancer cell growth through promoting Keap-1 S-glutathionylation and inducing apoptosis[J]. RSC Adv, 2018, 8: 792-804.
[9] Song H, Xu T, Feng X, et al. Itaconate prevents abdominal aortic aneurysm formation through inhibiting inflammation via activation of Nrf2[J]. EBioMedicine, 2020, 57: 102832. doi:10.1016/j.ebiom.2020.102832.
[10] Małecki JM, Davydova E, Falnes PØ. Protein methylation in mitochondria[J]. J Biol Chem, 2022, 298: 101791. doi:10.1016/j.jbc.2022.101791.
[11] Wang Z, Li R, Hou N, et al. PRMT5 reduces immunotherapy efficacy in triple-negative breast cancer by methylating KEAP1 and inhibiting ferroptosis[J]. J Immunother Cancer, 2023, 11. doi:10.1136/jitc-2023-006890.
[12] Yang H, Du Y, Fei X, et al. SUMOylation of the ubiquitin ligase component KEAP1 at K39 upregulates NRF2 and its target function in lung cancer cell proliferation[J]. J Biol Chem, 2023, 299: 105215. doi:10.1016/j.jbc.2023.105215.
[13] Adam J, Hatipoglu E, O′Flaherty L, et al. Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling[J]. Cancer Cell, 2011, 20: 524-537.
[14] Karuppagounder SS, Wang H, Kelly T, et al. The c-Abl inhibitor IkT-148009 suppresses neurodegeneration in mouse models of heritable and sporadic Parkinson′s disease[J]. Sci Transl Med, 2023, 15: eabp9352. doi:10.1126/scitranslmed.abp9352.
[15] Carvalho AN, Marques C, Guedes RC, et al. S-Glutathionylation of Keap1: a new role for glutathione S-transferase pi in neuronal protection[Z]. FEBS Lett, 2016: 590, 1455-1466.
[16] Zhang X, Feng N, Liu Y, et al. Neuroinflammation inhibition by small-molecule targeting USP7 noncatalytic domain for neurodegenerative disease therapy[J]. Sci Adv, 2022, 8: eabo789. doi:10.1126/sciadv.abo0789.
[17] Mills EL, Ryan DG, Prag HA, et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1[J]. Nature, 2018, 556: 113-117.
[18] Song Y, Xu Z, Zhong Q, et al. Sulfur signaling pathway in cardiovascular disease[J]. Front Pharmacol, 2023, 14: 1303465.doi:10.3389/fphar.2023.1303465.
[19] Xie L, Gu Y, Wen M, et al. Hydrogen sulfide induces Keap1 S-sulfhydration and suppresses diabetes-accele-rated atherosclerosis via Nrf2 activation[J]. Diabetes, 2016, 65: 3171-3184.
[20] 乔钰惠,孟增慧,郭丽君,等. 心肌缺血再灌注损伤的机制和治疗[J]. 基础医学与临床, 2015, 35: 1666-1671.
[21] Wang D, Yin Y, Wang S, et al. FGF1(ΔHBS) prevents diabetic cardiomyopathy by maintaining mitochondrial homeostasis and reducing oxidative stress via AMPK/Nur77 suppression[J]. Signal Transduct Target Ther, 2021, 6: 133. doi:10.1038/s41392-021-00542-2.
[22] Xiao C, Xia M, Wang J, et al. Luteolin attenuates cardiac ischemia/reperfusion injury in diabetic rats by modulating Nrf2 antioxidative function[J]. Oxid Med Cell Longev, 2019, 2019: 2719252. doi:10.1155/2019/2719252.
[23] Chen S, Chen L, Jiang H. Prognosis and risk factors of chronic kidney disease progression in patients with diabetic kidney disease and non-diabetic kidney disease: a prospective cohort CKD-ROUTE study[J]. Ren Fail, 2022, 44: 1309-1318.
[24] Xu T, Du Y, Sheng Z, et al. OGT-Mediated KEAP1 glycosylation accelerates NRF2 degradation leading to high phosphate-induced vascular calcification in chronic kidney disease[J]. Front Physiol, 2020, 11: 1092. doi:10.3389/fphys.2024.1505634.
[25] Wan H, Cai Y, Xiao L, et al. JFD, a novel natural inhibitor of Keap1 alkylation, suppresses intracellular mycobacterium tuberculosis growth through Keap1/Nrf2/SOD2-mediated ROS accumulation[J]. Oxid Med Cell Longev, 2023, 2023: 6726654. doi:10.1155/2023/6726654.

Keap1翻译后修饰调控氧化应激相关疾病

Post-translational modification of Keap1 regulates oxidative stress-related diseases

PDF

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价

[1]	杨瀚毅, 宁佳怡, 汪小兰, 张益萌, 谢婷珂, 陈奕玄, 韩静. 褪黑素抑制H₂O₂诱导的人脐静脉内皮细胞氧化应激及凋亡标志蛋白质的表达[J]. 基础医学与临床, 2024, 44(5): 645-650.
[2]	王瑞, 李蕊, 李运龙, 张玉萍, 于康, 刘燕萍. 锶与妊娠及妊娠期疾病的研究进展[J]. 基础医学与临床, 2024, 44(4): 428-433.
[3]	张威威, 谢婧, 李丽华. 帕立骨化醇抑制氧化应激减轻小鼠肝细胞紧密连接受损[J]. 基础医学与临床, 2024, 44(3): 317-324.
[4]	张秀丽, 胡孝刚, 莫俊, 陈铃. 冠心宁片减轻大鼠颈动脉粥样硬化斑块损伤[J]. 基础医学与临床, 2024, 44(2): 192-198.
[5]	牟杨, 杨志文. 右美托咪定通过激活AMPK减轻TNF-α诱导人成神经细胞瘤细胞系SH-SY5Y损伤[J]. 基础医学与临床, 2024, 44(2): 147-153.
[6]	张晓东, 李文冬, 陈景荷, 张艳琴. 山茱萸总苷抑制高糖诱导的人肾小管上皮细胞系HK-2凋亡和氧化损伤[J]. 基础医学与临床, 2024, 44(12): 1644-1650.
[7]	童玲, 张靖雯, 李帅, 段开鹏. 砷致胃癌的作用机制[J]. 基础医学与临床, 2024, 44(11): 1598-1602.
[8]	田宗源, 李展, 刘瑞霞. TERT调控线粒体氧化应激在疾病中的作用[J]. 基础医学与临床, 2024, 44(10): 1436-1441.
[9]	陈新军, 王卿语, 陈乐, 古春昱, 武卓. 紫檀茋减轻百草枯诱导的模型大鼠肺纤维化[J]. 基础医学与临床, 2023, 43(9): 1383-1389.
[10]	王琼, 董倩兰, 朱燕亭, 金刚, 张琳萍. 桔梗皂苷D减轻大鼠肾缺血/再灌注损伤[J]. 基础医学与临床, 2023, 43(8): 1222-1228.
[11]	杨为祝, 刘忠, 张峰林, 黄延林, 孙瑾, 田新华. NOX4介导的氧化应激参与垂体腺瘤出血性卒中的发生[J]. 基础医学与临床, 2023, 43(7): 1040-1044.
[12]	汪博, 张明焕. CIRC_0044235靶向miR-574-5p减轻IL-1β诱导的人软骨细胞损伤[J]. 基础医学与临床, 2023, 43(3): 419-426.
[13]	张梦瑶, 牛姝, 蔡静, 张立香, 赵志刚. 丹参酮ⅡA减轻高糖诱导的小鼠足细胞系PMC-5凋亡和氧化应激反应[J]. 基础医学与临床, 2023, 43(2): 277-282.
[14]	何綦琪, 吴晃, 李昱卓, 包军胜. 线粒体功能障碍在肾结石成石中作用的研究进展[J]. 基础医学与临床, 2023, 43(2): 306-310.
[15]	方思尹, 刘辰, 吴晋晖. 微管抑制剂在血管新生性疾病中的作用机制研究进展[J]. 基础医学与临床, 2023, 43(2): 327-331.