Transcription Factor Nrf1 Mediates the Proteasome Recovery Pathway after Proteasome Inhibition in Mammalian Cells

Abstract

SUMMARY In Saccharomyces cerevisiae, chemical or genetic inhibition of proteasome activity induces new proteasome synthesis promoted by the transcription factor RPN4. This ensures that proteasome activity is matched to demand. This transcriptional feedback loop is conserved in mammals, but its molecular basis is not understood. Here we report that Nuclear factor erythroid derived 2-related factor 1 (Nrf1), a transcription factor of the cap ‘n’ collar basic leucine zipper family, but not the related Nrf2, is necessary for induced proteasome gene transcription in mouse embryonic fibroblasts (MEFs). Promoter-reporter assays revealed the importance of antioxidant response elements in Nrf1-mediated upregulation of proteasome subunit genes. Nrf1-/- MEFs were impaired in the recovery of proteasome activity after transient treatment with the covalent proteasome inhibitor YU101 and knockdown of Nrf1 in human cancer cells enhanced cell killing by YU101. Taken together, our results suggest that Nrf1-mediated proteasome homeostasis could be an attractive target for therapeutic intervention in cancer.

Loss of nuclear factor E2-related factor 1 in the brain leads to dysregulation of proteasome gene expression and neurodegeneration

“…Aside from its role in constitutive expression of proteasome genes, we have also demonstrated that Nrf1 is required for inhibitor-induced proteasome gene expression (28). On the basis of these findings, we propose that Nrf1 is essential for expression of mammalian 26S proteasome under basal as well as stress-induced conditions.…”

Profiling human protein degradome delineates cellular responses to proteasomal inhibition and reveals a feedback mechanism in regulating proteasome homeostasis

“…This mechanism might also function in concert with the previously demonstrated transcriptional regulation [52,53] to form a feedback loop regulating proteasome homeostasis ( Figure 5E), which could upregulate proteasome function and functionally compensate for BTZ-induced compromise in proteolytic capacity. This may collectively reduce BTZ cytotoxicity, thus providing an additional avenue for drug resistance in BTZ-treated cancer cells.…”

“…Proteasomal inhibition was found to activate Nrf1- [52] or Nrf2-mediated [53] transcription of some proteasome subunits, which gave rise to the so-called "proteasome bounce-back response". Overexpression of or mutations in PSMB5 gene were also reported in BTZ-resistant cancer cells [3,54,55].…”

“…BTZ treatment was found to only slightly stabilize free PSMC1 proteins, but significantly increased its levels in the PSMB5 co-immunoprecipitates, suggesting that more functional proteasome complexes might be assembled in cells treated with BTZ (Supplementary information, Figure S6F). Conceivably, mechanisms of both transcriptional activation [52,53,57] and the stabilizing effect of BTZ might work concertedly to modulate proteasome homeostasis in these myeloma cells.…”

Inflammatory Macrophages Induce Nrf2 Transcription Factor-dependent Proteasome Activity in Colonic NCM460 Cells and Thereby Confer Anti-apoptotic Protection

“…To some extent, this protective effect against apoptosis could be attributed to the Nrf2-induced expression of proteasomal genes leading to an elevated proteasome activity in tumor cells (11, 19 -24). Whereas this proteasome inducing effect of Nrf2 in response to oxidative and electrophilic stress has been widely reported already (11,(25)(26)(27)(28)(29)(30), recent data revealed that the closely related transcription factor Nrf1 (TCF11) plays a particular role in the maintenance of constitutive proteasome activity (31). Moreover, Nrf1 mediates the inducing effect of proteasome inhibitors on proteasomal gene expression to a greater extent than Nrf2 (31,32).…”