The aspartyl protease DDI2 activates Nrf1 to compensate for proteasome dysfunction
- The University of Tokyo, Japan
Abstract
In response to proteasome dysfunction, mammalian cells upregulate proteasome gene expression by activating Nrf1. Nrf1 is an endoplasmic reticulum-resident transcription factor that is continually retrotranslocated and degraded by the proteasome. Upon proteasome inhibition, Nrf1 escapes degradation and is cleaved to become active. However, the processing enzyme for Nrf1 remains obscure. Here we show that the aspartyl protease DNA-damage inducible 1 homolog 2 (DDI2) is required to cleave and activate Nrf1. Deletion of DDI2 reduced the cleaved form of Nrf1 and increased the full-length cytosolic form of Nrf1, resulting in poor upregulation of proteasomes in response to proteasome inhibition. These defects were restored by adding back wild-type DDI2 but not protease-defective DDI2. Our results provide a clue for blocking compensatory proteasome synthesis to improve cancer therapies targeting proteasomes.
Article and author information
Author details
Funding
Japan Society for the Promotion of Science (25221102)
- Shigeo Murata
Japan Society for the Promotion of Science (26000014)
- Shigeo Murata
Takeda Science Foundation
- Shigeo Murata
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Ivan Dikic, Goethe University Medical School, Germany
Version history
- Received: May 31, 2016
- Accepted: August 12, 2016
- Accepted Manuscript published: August 16, 2016 (version 1)
- Accepted Manuscript updated: August 19, 2016 (version 2)
- Version of Record published: August 26, 2016 (version 3)
Copyright
© 2016, Koizumi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The aspartyl protease DDI2 activates Nrf1 to compensate for proteasome dysfunction
eLife 5:e18357.
https://doi.org/10.7554/eLife.18357
