The proximity-based protein interactome and regulatory logics of the transcription factor p65 NF-κB/RELA.

IF 6.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY EMBO Reports Pub Date : 2025-01-03 DOI:10.1038/s44319-024-00339-8

Lisa Leib, Jana Juli, Liane Jurida, Christin Mayr-Buro, Jasmin Priester, Hendrik Weiser, Stefanie Wirth, Simon Hanel, Daniel Heylmann, Axel Weber, M Lienhard Schmitz, Argyris Papantonis, Marek Bartkuhn, Jochen Wilhelm, Uwe Linne, Johanna Meier-Soelch, Michael Kracht

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Abstract

The protein interactome of p65/RELA, the most active subunit of the transcription factor (TF) NF-κB, has not been previously determined in living cells. Using p65-miniTurbo fusion proteins and biotin tagging, we identify >350 RELA interactors from untreated and IL-1α-stimulated cells, including many TFs (47% of all interactors) and >50 epigenetic regulators belonging to different classes of chromatin remodeling complexes. A comparison with the interactomes of two point mutants of p65 reveals that the interactions primarily require intact dimerization rather than DNA-binding properties. A targeted RNAi screen for 38 interactors and subsequent functional transcriptome and bioinformatics studies identify gene regulatory (sub)networks, each controlled by RELA in combination with one of the TFs ZBTB5, GLIS2, TFE3/TFEB, or S100A8/A9. The large, dynamic and versatile high-resolution interactome of RELA and its gene regulatory logics provides a rich resource and a new framework for explaining how RELA cooperativity determines gene expression patterns.

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转录因子p65 NF-κB/RELA的邻近蛋白相互作用及其调控逻辑。

p65/RELA是转录因子（TF） NF-κB最活跃的亚基，其蛋白相互作用组在活细胞中尚未被确定。利用p65-miniTurbo融合蛋白和生物素标记，我们从未经处理和il -1α刺激的细胞中鉴定出bbbb350 RELA相互作用因子，包括许多tf（占所有相互作用因子的47%）和bbbb50属于不同类别的染色质重塑复合物的表观遗传调节因子。与p65的两个点突变体的相互作用组的比较表明，相互作用主要需要完整的二聚化而不是dna结合特性。对38个相互作用物的靶向RNAi筛选以及随后的功能转录组和生物信息学研究确定了基因调控（亚）网络，每个网络由RELA与TFs之一ZBTB5， GLIS2， TFE3/TFEB或S100A8/A9联合控制。RELA庞大、动态、多功能的高分辨率相互作用组及其基因调控逻辑为解释RELA协同作用如何决定基因表达模式提供了丰富的资源和新的框架。

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来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

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