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Published September 26, 2016 | Accepted Version + Supplemental Material
Journal Article Open

Nrf1 can be processed and activated in a proteasome-independent manner


In response to proteasome inhibition, the transcription factor Nrf1 facilitates de novo synthesis of proteasomes by inducing proteasome subunit (PSM) genes 1 and 2. Previously, we showed that activation of the p120 form of Nrf1, a membrane-bound protein in the endoplasmic reticulum (ER) with the bulk of its polypeptide in the lumen, involves its retrotranslocation into the cytosol in a manner that depends on the AAA-ATPase p97/VCP [3]. This is followed by proteolytic processing and mobilization of the transcriptionally active p110 form of Nrf1 to the nucleus. A subsequent study suggested that site-specific proteolytic processing of Nrf1 by the proteasome yields an active 75 kDa fragment [4]. We show here that under conditions where all three active sites of the proteasome are completely blocked, p120 Nrf1 can still be proteolytically cleaved to the p110 form, which is translocated to the nucleus to activate transcription of PSM genes. Thus, our results indicate that a proteasome-independent pathway can promote the release of active p110 Nrf1 from the ER membrane.

Additional Information

© 2016 Elsevier Ltd. Available online 26 September 2016. Microscopy was performed at VCU's Microscopy Core, supported in part by funding from NIH-NINDS (5P30-NS047463) and from NCI (P30-CA016059). S.K.R. is supported by NCI's K99/R00 award (R00CA154884). R.J.D. is a HHMI investigator. E.K. was supported by grants of the DFG (SFB740, KR1915/5-1). R.J.D. is a founder, shareholder, and member of the scientific advisory board of Cleave Biosciences. Author Contributions: S.K.R., R.J.D., and E.K. designed experiments and analyzed results; J.R.V. and F.S. performed experiments; S.K.R. and R.J.D. wrote the manuscript.

Attached Files

Accepted Version - nihms-809062.pdf

Supplemental Material - mmc1.pdf


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August 20, 2023
October 20, 2023