Regulation of NRF1, a master transcription factor of proteasome genes: implications for cancer and neurodegeneration.
Regulation of NRF1, a master transcription factor of proteasome genes: implications for cancer and neurodegeneration.
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DOI：
10.1091/mbc.e20-04-0238
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发表时间：
2020-09-15
影响因子：
3.3
通讯作者：
Radhakrishnan SK
中科院分区：
文献类型：
--
作者：
Northrop A;Byers HA;Radhakrishnan SK
感知蛋白酶体不足并通过指导从头蛋白酶体的转录合成来响应的能力是进化中保守的特征，并且在从酵母到人类的生物体中发现。哺乳动物细胞中的这种稳态机制由转录因子NRF 1驱动。有趣的是，NRF 1作为内质网（ER）膜蛋白合成，并且当细胞蛋白酶体活性足够时，其被逆转运到细胞溶质中并被ER-ER相关降解途径（ERAD）靶向破坏。然而，当蛋白酶体能力减弱时，反转录易位的NRF 1逃避ERAD并被激活为成熟的转录因子，其穿过细胞核以诱导蛋白酶体基因。在这个角度来看，我们跟踪的旅程NRF 1从ER到细胞核，特别关注的各种分子调节剂，它遇到沿着。此外，使用人类病理学，如癌症和神经退行性疾病为例，我们探讨的概念，调节NRF 1-蛋白酶体轴可以提供一个可行的治疗策略在这些情况下的基础。
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.