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Published January 21, 2014 | Published
Journal Article Open

p97-dependent retrotranslocation and proteolytic processing govern formation of active Nrf1 upon proteasome inhibition


Proteasome inhibition elicits an evolutionarily conserved response wherein proteasome subunit mRNAs are upregulated, resulting in recovery (i.e., 'bounce-back') of proteasome activity. We previously demonstrated that the transcription factor Nrf1/NFE2L1 mediates this homeostatic response in mammalian cells. We show here that Nrf1 is initially translocated into the lumen of the ER, but is rapidly and efficiently retrotranslocated to the cytosolic side of the membrane in a manner that depends on p97/VCP. Normally, retrotranslocated Nrf1 is degraded promptly by the proteasome and active species do not accumulate. However, in cells with compromised proteasomes, retrotranslocated Nrf1 escapes degradation and is cleaved N-terminal to Leu-104 to yield a fragment that is no longer tethered to the ER membrane. Importantly, this cleavage event is essential for Nrf1-dependent activation of proteasome gene expression upon proteasome inhibition. Our data uncover an unexpected role for p97 in activation of a transcription factor by relocalizing it from the ER lumen to the cytosol.

Additional Information

© 2014 Radhakrishnan et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Received: 08 November 2013; Accepted: 04 December 2013; Published: 21 January 2014. We are grateful to the members of the Deshaies' lab for helpful advice and critical reading of the manuscript. We thank R Rawson (UT Southwestern Medical Center at Dallas) for testing Nrf1 processing in S1P/S2P deficient CHO cells. We gratefully acknowledge the help of J Zhou and F Rusnak (Protein/ Peptide Micro Analytical Laboratory, California Institute of Technology) for N-terminal sequencing of Nrf1. We thank Han-Jie Zhou and BioDuro, LLC for the synthesis of Rhomboid inhibitor. We thank Lev G Lis and Michael A Walters (University of Minnesota) for the synthesis of NMS-873. RJD is a Howard Hughes Medical Institute (HHMI) Investigator, and this work was supported in part by HHMI. Author contributions: SKR, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article; WB, Analysis and interpretation of data, Contributed unpublished essential data or reagents; RJD, Conception and design, Analysis and interpretation of data, Drafting or revising the article. Competing interests: RJD: RJD is a founder and shareholder of Cleave Biosciences, and an eLife reviewing editor. The other authors declare that no competing interests exist

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