Abstract
Inhibition of the proteasome leads to proteotoxic stress, which is characterized by the buildup of ubiquitinated proteins that cannot be degraded properly. The transcription factor Nrf1 (also called NFE2L1) counteracts proteotoxic stress by inducing transcription of proteasome subunit genes, resulting in the restoration of proteasome activity. Further understanding of the Nrf1 pathway is therefore of interest in both neurodegeneration, where proteasome activity could be enhanced, and cancer, where suppression of this pathway could potentiate the cell-killing effect mediated by proteasome inhibitor drugs. Here, to identify novel regulators of Nrf1, we performed an RNAi screen in an engineered cell line, reporting on Nrf1 transcriptional activity. In addition to validating known regulators, we discovered that the AAA+ ATPase RUVBL1 is necessary for Nrf1's transcriptional activity. Given that RUVBL1 is part of different multisubunit complexes that play key roles in transcription, we dissected this phenomenon further and found that the TIP60 chromatin-regulatory complex is essential for Nrf1-dependent transcription of proteasome genes. Consistent with these observations, Nrf1, RUVBL1, and TIP60 proteins were co-recruited to the promoter regions of proteasome genes after proteasome inhibitor treatments. More importantly, depletion of RUVBL1 or TIP60 in various cancer cells sensitized them to cell death induced by proteasome inhibition. Overall, our study provides a framework for manipulating the TIP60-Nrf1 axis to alter proteasome function in various human diseases, including cancer.
Highlights
Inhibition of the proteasome leads to proteotoxic stress, which is characterized by the buildup of ubiquitinated proteins that cannot be degraded properly
Nrf1 has emerged as a critical transcription factor in the cellular arsenal to combat proteotoxic stress or proteasome insufficiency
Several previous studies, including ours, have dissected the regulation of Nrf1 function that is achieved via multiple mechanisms in the cell: regulation of its abundance by the ubiquitin ligases HRD1, FBXW7, and -TRCP; regulation of its extraction from the endoplasmic reticulum (ER) by p97; regulation of its proteolytic processing by DDI2; regulation of its deglycosylation by NGLY1; and regulation of its phosphorylation and, thereby, its transcriptional activity by casein kinase 2, to name a few [9, 14, 15]
Summary
Nrf1-mediated transcriptional regulation of the proteasome requires a functional TIP60 complex. Nrf1-dependent transcription requires TIP60 way to make this therapy more effective would be to devise strategies to block the Nrf pathway, impairing the ability of the cancer cells to recover their proteasome activity in response to inhibition of the proteasome In support of this notion, a recent study demonstrated that attenuation of Nrf activation via p97 inhibition increased the efficacy of proteasome inhibitor drugs in multiple myeloma models [18]. We identified a requirement for the TIP60 chromatin-modifying complex in enabling Nrf1-mediated proteasomal gene expression in response to inhibition of the proteasome This expands our view of the inner workings of Nrf1mediated transcription and could offer strategies to manipulate this pathway in human diseases
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