Chavarria Claire, Zaffalon Léa, Ribeiro Sérgio T, Op Mélanie, Quadroni Manfredo, Iatrou Maria Sofia, Chapuis Chloé, Martinon Fabio
Department of Immunobiology, University of Lausanne, 155 Ch. des Boveresses, 1066 Epalinges, Switzerland.
Protein Analysis Facility, Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
iScience. 2023 Aug 29;26(10):107777. doi: 10.1016/j.isci.2023.107777. eCollection 2023 Oct 20.
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 and 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.
转录因子NRF1定位于内质网（ER），并不断被转运至胞质溶胶进行蛋白酶体降解。然而，当蛋白酶体存在缺陷时，NRF1逃脱降解，并被蛋白酶DDI2进行蛋白水解切割，产生一种转录活性形式，从而恢复包括蛋白酶体功能在内的蛋白质稳态。调节NRF1蛋白水解激活和转录潜能的机制仍知之甚少。本研究表明，内质网通过E3泛素连接酶HRD1协调NRF1的泛素化，是NRF1功能的关键调节因子。我们发现，HRD1介导的NRF1泛素化对于细胞中DDI2介导的加工过程是必需的。此外，我们发现 和 的缺陷均会损害DDI2介导的NRF1加工过程，表明这些基因是DDI2蛋白水解机制的重要组成部分。我们的研究结果突出了内质网激活NRF1以协调细胞适应性反应转录活性的复杂机制。
