ER-trafficking triggers NRF1 ubiquitination to promote its proteolytic activation

Claire Chavarria; Léa Zaffalon; Sérgio T Ribeiro; Mélanie Op; Manfredo Quadroni; Maria Sofia Iatrou; Chloé Chapuis; Fabio Martinon

doi:10.1016/j.isci.2023.107777

ER-trafficking triggers NRF1 ubiquitination to promote its proteolytic activation

iScience. 2023 Aug 29;26(10):107777. doi: 10.1016/j.isci.2023.107777. eCollection 2023 Oct 20.

Authors

Claire Chavarria¹, Léa Zaffalon¹, Sérgio T Ribeiro¹, Mélanie Op¹, Manfredo Quadroni², Maria Sofia Iatrou¹, Chloé Chapuis¹, Fabio Martinon¹

Affiliations

¹ Department of Immunobiology, University of Lausanne, 155 Ch. des Boveresses, 1066 Epalinges, Switzerland.
² Protein Analysis Facility, Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.

Abstract

The transcription factor NRF1 resides in the endoplasmic reticulum (ER) and is constantly transported to the cytosol for proteasomal degradation. However, when the proteasome is defective, NRF1 escapes degradation and undergoes proteolytic cleavage by the protease DDI2, generating a transcriptionally active form that restores proteostasis, including proteasome function. The mechanisms that regulate NRF1 proteolytic activation and transcriptional potential remain poorly understood. This study demonstrates that the ER is a crucial regulator of NRF1 function by orchestrating its ubiquitination through the E3 ubiquitin ligase HRD1. We show that HRD1-mediated NRF1 ubiquitination is necessary for DDI2-mediated processing in cells. Furthermore, we found that deficiency in both RAD23A and RAD23B impaired DDI2-mediated NRF1 processing, indicating that these genes are essential components of the DDI2 proteolytic machinery. Our findings highlight the intricate mechanism by which the ER activates NRF1 to coordinate the transcriptional activity of an adaptation response in cells.

Keywords: Biochemistry; Biological sciences; Cell biology; Natural sciences.