Regulation of NRF1, a master transcription factor of proteasome genes: implications for cancer and neurodegeneration

Abstract

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.

FIGURE 1:

Molecular players involved in the NRF1 pathway. This model depicts our current understanding of the Nrf1 pathway. During biosynthesis, Nrf1 p120 is inserted into the endoplasmic reticulum (ER) membrane via the Sec61 pathway in a type II (C_lumen/N_cytosol) orientation. The domains close to the C-terminus of p120 are glycosylated in the ER lumen. Under unperturbed conditions, p120 is ubiquitinated by HRD1, retrotranslocated by the action of ATPase p97, deglycosylated by NGLY1, and degraded by the proteasome. When the proteasome is inhibited, retrotranslocated p120 is deglycosylated and additionally cleaved by the protease DDI2 and the active fragment p110 migrates to the nucleus to induce transcription of proteasome subunit (PSM) genes. The activity of Nrf1 p110 in the nucleus is influenced by cofactors such as small Maf (sMaf) proteins, TIP60, FBW7α, GSK3, β-TrCP, and USP15. Although CK2 is depicted in the nucleus, the compartment where it phosphorylates NRF1 is currently unclear. Details and references are provided in the text.