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

Vangala, Janakiram R. and Sotzny, Franziska and Krüger, Elke and Deshaies, Raymond J. and Radhakrishnan, Senthil K. (2016) Nrf1 can be processed and activated in a proteasome-independent manner. Current Biology, 26 (18). R834-R835. ISSN 0960-9822. PMCID PMC6156719.

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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.

Item Type:Article
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URLURL TypeDescription CentralArticle
Deshaies, Raymond J.0000-0002-3671-9354
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.
Funding AgencyGrant Number
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Deutsche Forschungsgemeinschaft (DFG)SFB740
Deutsche Forschungsgemeinschaft (DFG)KR1915/5-1
Issue or Number:18
PubMed Central ID:PMC6156719
Record Number:CaltechAUTHORS:20161003-085621178
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Official Citation:Janakiram R. Vangala, Franziska Sotzny, Elke Krüger, Raymond J. Deshaies, Senthil K. Radhakrishnan, Nrf1 can be processed and activated in a proteasome-independent manner, Current Biology, Volume 26, Issue 18, 26 September 2016, Pages R834-R835, ISSN 0960-9822, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:70748
Deposited By: Tony Diaz
Deposited On:03 Oct 2016 16:55
Last Modified:03 Oct 2019 16:00

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