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文昌鱼中KEAP1-NRF的原始途径：对抗氧化防御系统进化的启示

The Ancestral KEAP1-NRF Pathway in Amphioxus : Implications for the Evolution of Antioxidant Defense System.

作者信息

Li Weichen, Liang Xiaoqian, Xiang Keyu, Li Hongyan, Zhang Yu

机构信息

College of Marine Life Sciences, Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao 266003, China.

Key Laboratory of Evolution & Marine Biodiversity (Ministry of Education), Ocean University of China, Qingdao 266003, China.

出版信息

Int J Mol Sci. 2025 Apr 6;26(7):3427. doi: 10.3390/ijms26073427.

DOI:10.3390/ijms26073427
PMID:40244297
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11989980/
Abstract

The Kelch-like ECH-associated protein 1 (KEAP1)/Nuclear factor E2-related factor 2 (NRF2) pathway is a key mechanism that responds to oxidative stress and xenobiotic stimuli in vertebrates. However, knowledge of its evolutionary origins remains limited. In this study, we identify the ancestral homologues of KEAP1 and NRF (BjKEAP1 and BjNRF) in cephalochordate amphioxus (). BjNRF uniquely combines the feature domains of vertebrates NRF1 and NRF2, marking it as an evolutionary intermediate. High expression levels of 1 and in the gill, hepatic cecum, and intestine highlight their roles in environmental defense at key interface tissues. Functional studies reveal that BjKEAP1 regulates the cytoplasmic localization of BjNRF. Typical NRF2 activator sulforaphane (SFN) induces its nuclear translocation and significantly elevates the transcriptional expression of BjNRF and phase II detoxification enzymes. Moreover, exposure to the environmental toxin Benzo[a]pyrene (BaP) activates this stress response system. These findings bridge critical gaps in our understanding of this pathway in basal chordates and offer new insights into the evolutionary trajectory of the KEAP1-NRF system. Furthermore, this study highlights crucial implications for the conservation of amphioxus in deteriorating marine environments.

摘要

类 Kelch 样 ECH 相关蛋白 1（KEAP1）/核因子 E2 相关因子 2（NRF2）途径是脊椎动物中应对氧化应激和外源性刺激的关键机制。然而，对其进化起源的了解仍然有限。在本研究中，我们在头索动物文昌鱼中鉴定出 KEAP1 和 NRF 的祖先同源物（BjKEAP1 和 BjNRF）。BjNRF 独特地结合了脊椎动物 NRF1 和 NRF2 的特征结构域，表明它是一种进化中间体。BjKEAP1 和 BjNRF 在鳃、肝盲囊和肠道中的高表达水平突出了它们在关键界面组织的环境防御中的作用。功能研究表明，BjKEAP1 调节 BjNRF 的细胞质定位。典型的 NRF2 激活剂萝卜硫素（SFN）诱导其核转位，并显著提高 BjNRF 和 II 期解毒酶的转录表达。此外，暴露于环境毒素苯并[a]芘（BaP）会激活这个应激反应系统。这些发现填补了我们对基础脊索动物中该途径理解的关键空白，并为 KEAP1-NRF 系统的进化轨迹提供了新的见解。此外，这项研究突出了文昌鱼在不断恶化的海洋环境中的保护的关键意义。

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