The ability to sense proteasome insufficiency and respond by directing the transcriptional synthesis of de novo proteasomes is a trait that is conserved in evolution and is found in organisms ranging from yeast to humans. This homeostatic mechanism in mammalian cells is driven by the transcription factor NRF1. Interestingly, NRF1 is synthesized as an endoplasmic reticulum (ER) membrane protein and when cellular proteasome activity is sufficient, it is retrotranslocated into the cytosol and targeted for destruction by the ER-­associated degradation pathway (ERAD). However, when proteasome capacity is diminished, retrotranslocated NRF1 escapes ERAD and is activated into a mature transcription factor that traverses to the nucleus to induce proteasome genes. In this Perspective, we track the journey of NRF1 from the ER to the nucleus, with a special focus on the various molecular regulators it encounters along its way. Also, using human pathologies such as cancer and neurodegenerative diseases as examples, we explore the notion that modulating the NRF1-proteasome axis could provide the basis for a viable therapeutic strategy in these cases.

感觉蛋白酶体不足和通过指导从头蛋白酶体的转录合成反应的能力是在进化中保守的特性，并且存在于从酵母到人类的各种生物中。哺乳动物细胞中的这种稳态机制是由转录因子NRF1驱动的。有趣的是，NRF1合成为内质网（ER）膜蛋白，当细胞蛋白酶体的活性足够时，它会逆向转运到细胞质中，并被ER相关降解途径（ERAD）破坏。但是，当蛋白酶体能力降低时，逆转位的NRF1逃离ERAD并被激活为成熟的转录因子，该转录因子穿越细胞核诱导蛋白酶体基因。在此透视图中，我们跟踪NRF1从ER到核的过程，特别关注其在使用过程中遇到的各种分子调节剂。同样，以人类病理学（例如癌症和神经退行性疾病）为例，我们探讨了调节NRF1蛋白酶体轴可以为这些情况下可行的治疗策略提供基础的观念。