The Casein Kinase 2-Nrf1 Axis Controls the Clearance of Ubiquitinated Proteins by Regulating Proteasome Gene Expression

Abstract

Impairment of the ubiquitin-proteasome system (UPS) has been implicated in the pathogenesis of human diseases, including neurodegenerative disorders. Thus, stimulating proteasome activity is a promising strategy to ameliorate these age-related diseases. Here we show that the protein kinase casein kinase 2 (CK2) regulates the transcriptional activity of Nrf1 to control the expression of the proteasome genes and thus the clearance of ubiquitinated proteins. We identify CK2 as an Nrf1-binding protein and find that the knockdown of CK2 enhances the Nrf1-dependent expression of the proteasome subunit genes. Real-time monitoring of proteasome activity reveals that CK2 knockdown alleviates the accumulation of ubiquitinated proteins upon proteasome inhibition. Furthermore, we identify Ser 497 of Nrf1 as the CK2 phosphorylation site and demonstrate that its alanine substitution (S497A) augments the transcriptional activity of Nrf1 and mitigates proteasome dysfunction and the formation of p62-positive juxtanuclear inclusion bodies upon proteasome inhibition. These results indicate that the CK2-mediated phosphorylation of Nrf1 suppresses the proteasome gene expression and activity and thus suggest that the CK2-Nrf1 axis is a potential therapeutic target for diseases associated with UPS impairment.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01271-12.

ACKNOWLEDGMENTS

We are grateful to David Piwnica-Worms and Raymond J. Deshaies for the Ub-FL plasmid and the 3xPSMA4-ARE-Luc plasmid, respectively. We also thank Noriko Noguchi and Akiko Matsumoto for research support.

This work was supported in part by grants-in-aid (A.K. and Y.T.) and the Strategic Research Foundation at Private Universities (2012 to 2016) (A.K.) from the Ministry of Education, Sports, Science and Technology, the Mochida Memorial Foundation (A.K.), the Naito Foundation (A.K.), the Suzuken Memorial Foundation (A.K.), the Takeda Science Foundation (A.K.), the Uehara Memorial Foundation (A.K.), Astellas Foundation for Research on Metabolic Disorders (A.K.), and the Inamori Foundation (Y.T.).