Antitumor transcription activator NFE2L1, with the functions to regulate redox homeostasis, protein turnover, and material metabolism, plays an important role in embryonic development and specialization of tissue and organ functions. Deficiency of NFE2L1 gene in different regions yields distinct phenotypes, suggesting that NFE2L1 may have a transcription factor-independent function. Here we originally discovered the non-transcription factor activity of NFE2L1 by constructing a truncated protein-NFE2L1ΔC without 152 aa at the C-terminus which lost the transcription factor activity. The regulation of NFE2L1 on redox homeostasis, proteasome function, and immune response mainly depends on its transcription activator function in nucleus, while the regulation on metabolism, ribosome function, and canceration is germanely to its non-transcription factor activity in cytoplasm. Surprisingly, the results indicated the tumor suppressive effect of NFE2L1 by repression of Wnt/β-catenin signaling in a non-transcription factor manner, indicating the potential value of NFE2L1 as a therapeutic target in clinical cancer treatment independent of its transcription factor activity. Our observations reveal the non-transcription factor activity of NFE2L1 for the first time, and lay foundation for the basic and applied research of NFE2L1.

中文翻译：

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抗肿瘤转录激活因子NFE2L1非转录因子活性的最初发现使其功能扩展

抗肿瘤转录激活因子NFE2L1具有调节氧化还原稳态，蛋白质更新和物质代谢的功能，在胚胎发育以及组织和器官功能的专门化中起着重要作用。NFE2L1基因在不同区域的缺陷产生不同的表型，这表明NFE2L1可能具有转录因子非依赖性功能。在这里，我们最初通过构建在C末端缺失152 aa的截短蛋白-NFE2L1ΔC来发现NFE2L1的非转录因子活性，该蛋白缺失了转录因子的活性。NFE2L1对氧化还原稳态，蛋白酶体功能和免疫反应的调节主要取决于其在核中的转录激活子功能，而对代谢，核糖体功能，癌变与其在细胞质中的非转录因子活性密切相关。令人惊讶地，结果表明通过以非转录因子方式抑制Wnt /β-catenin信号传导来抑制NFE2L1的肿瘤抑制作用，表明了NFE2L1作为临床靶标中的治疗靶标的潜在价值，与其转录因子活性无关。我们的观察首次揭示了NFE2L1的非转录因子活性，为NFE2L1的基础和应用研究奠定了基础。