ABSTRACT
Eukaryotic cells maintain protein homeostasis through the activity of multiple basal and inducible systems, which function in concert to allow cells to adapt to a wide range of environmental conditions. Although the transcriptional programs regulating individual pathways have been studied in detail, it is not known how the different pathways are transcriptionally integrated such that a deficiency in one pathway can be compensated by a change in an auxiliary response. One such pathway that plays an essential role in many proteostasis responses is the ubiquitin-proteasome system, which functions to degrade damaged, unfolded, or short half-life proteins. Transcriptional regulation of the proteasome is mediated by the transcription factor Nrf1. Using a conditional knockout mouse model, we found that Nrf1 regulates protein homeostasis in the endoplasmic reticulum (ER) through transcriptional regulation of the ER stress sensor ATF6. In Nrf1 conditional-knockout mice, a reduction in proteasome activity is accompanied by an ATF6-dependent downregulation of the endoplasmic reticulum-associated degradation machinery, which reduces the substrate burden on the proteasome. This indicates that Nrf1 regulates a homeostatic shift through which proteostasis in the endoplasmic reticulum and cytoplasm are coregulated based on a cell's ability to degrade proteins.
Supplemental material for this article may be found at https://doi.org/10.1128/MCB.00439-16.
ACKNOWLEDGMENTS
We thank M. Tsuda, M. Kikuchi, M. Nakagawa, and K. Kuroda for technical assistance and S. Goto for assistance with the mouse work. We also acknowledge the technical support of the Biomedical Research Core of Tohoku University Graduate School of Medicine and all members of the Department of Medical Biochemistry laboratory for valuable discussions.
This study was supported in part by Platform for Drug Discovery, Informatics, and Structural Life Science from the MEXT, Japan (T.T. and M.Y.), JSPS KAKENHI grant 25750357 (T.T.), and the Adaptable and Seamless Technology Transfer Program through target-driven R&D (A-STEP), Japan Science and Technology Agency grant J120001909 (T.T.).