NRF家族的近似蛋白质组分析发现帕金森病蛋白ZNF746/PARIS是NRF2的共复合抑制因子

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling Pub Date : 2023-12-12 DOI:10.1126/scisignal.adi9018

Kyle M. LaPak, Soma Saeidi, Ilah Bok, Nathan T. Wamsley, Isaac B. Plutzer, Dhaval P. Bhatt, Jingqin Luo, Ghazaleh Ashrafi, M. Ben Major

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引用次数: 0

摘要

核因子红细胞 2 相关因子 2（NRF2）转录因子能激活细胞保护和代谢基因的表达，以应对各种亲电压力源。NRF2 的连续活性会促进癌症进展，而 NRF2 功能的降低则会导致神经退行性疾病。我们利用近距离蛋白质组分析确定了 NRF2 及其家族成员 NRF1、NRF3 和 NRF2 异源二聚体 MAFG 的蛋白质网络。对共复合蛋白的功能筛选揭示了之前未表征的 NRF2 转录活性调节因子。我们发现，ZNF746（又称 PARIS）是一种与帕金森病有关联的锌指转录因子，它与 NRF2 和 MAFG 有物理关联，从而抑制了 NRF2 驱动的转录。在帕金森病的神经元细胞模型中，ZNF746 的过表达增加了氧化应激和细胞凋亡，而这些表型可通过化学和遗传方法过度激活 NRF2 而逆转。这项研究提供了一个功能注释的 NRF2 邻近网络，并提出了帕金森病中 ZNF746 过表达与抑制 NRF2 驱动的神经保护之间的联系。

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Proximity proteomic analysis of the NRF family reveals the Parkinson’s disease protein ZNF746/PARIS as a co-complexed repressor of NRF2

The nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor activates cytoprotective and metabolic gene expression in response to various electrophilic stressors. Constitutive NRF2 activity promotes cancer progression, whereas decreased NRF2 function contributes to neurodegenerative diseases. We used proximity proteomic analysis to define protein networks for NRF2 and its family members NRF1, NRF3, and the NRF2 heterodimer MAFG. A functional screen of co-complexed proteins revealed previously uncharacterized regulators of NRF2 transcriptional activity. We found that ZNF746 (also known as PARIS), a zinc finger transcription factor implicated in Parkinson’s disease, physically associated with NRF2 and MAFG, resulting in suppression of NRF2-driven transcription. ZNF746 overexpression increased oxidative stress and apoptosis in a neuronal cell model of Parkinson’s disease, phenotypes that were reversed by chemical and genetic hyperactivation of NRF2. This study presents a functionally annotated proximity network for NRF2 and suggests a link between ZNF746 overexpression in Parkinson’s disease and inhibition of NRF2-driven neuroprotection.

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来源期刊

Science Signaling BIOCHEMISTRY & MOLECULAR BIOLOGY-CELL BIOLOGY

CiteScore

9.50

自引率

0.00%

发文量

148

审稿时长

3-8 weeks

期刊介绍： "Science Signaling" is a reputable, peer-reviewed journal dedicated to the exploration of cell communication mechanisms, offering a comprehensive view of the intricate processes that govern cellular regulation. This journal, published weekly online by the American Association for the Advancement of Science (AAAS), is a go-to resource for the latest research in cell signaling and its various facets. The journal's scope encompasses a broad range of topics, including the study of signaling networks, synthetic biology, systems biology, and the application of these findings in drug discovery. It also delves into the computational and modeling aspects of regulatory pathways, providing insights into how cells communicate and respond to their environment. In addition to publishing full-length articles that report on groundbreaking research, "Science Signaling" also features reviews that synthesize current knowledge in the field, focus articles that highlight specific areas of interest, and editor-written highlights that draw attention to particularly significant studies. This mix of content ensures that the journal serves as a valuable resource for both researchers and professionals looking to stay abreast of the latest advancements in cell communication science.