The aspartyl protease DDI2 activates Nrf1 to compensate for proteasome dysfunction

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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.

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Shun Koizumi

Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Taro Irie

Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Shoshiro Hirayama

Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Yasuyuki Sakurai

Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Hideki Yashiroda

Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Isao Naguro

Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Hidenori Ichijo

Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Jun Hamazaki

Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Shigeo Murata

Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

For correspondence
smurata@mol.f.u-tokyo.ac.jp

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3177-3503

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.

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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.