The aspartyl protease DDI2 drives adaptation to proteasome inhibition in multiple myeloma.

Details

Serval ID
serval:BIB_A9FBE08A94DB
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
The aspartyl protease DDI2 drives adaptation to proteasome inhibition in multiple myeloma.
Journal
Cell death & disease
Author(s)
Op M., Ribeiro S.T., Chavarria C., De Gassart A., Zaffalon L., Martinon F.
ISSN
2041-4889 (Electronic)
Publication state
Published
Issued date
19/05/2022
Peer-reviewed
Oui
Volume
13
Number
5
Pages
475
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
Proteasome inhibitors, such as bortezomib, are first-line therapy against multiple myeloma (MM). Unfortunately, patients frequently become refractory to this treatment. The transcription factor NRF1 has been proposed to initiate an adaptation program that regulates proteasome levels. In the context of proteasome inhibition, the cytosolic protease DDI2 cleaves NRF1 to release an active fragment that translocates to the nucleus to promote the transcription of new proteasome subunits. However, the contribution of the DDI2-NRF1 pathway to bortezomib resistance is poorly understood. Here we show that upon prolonged bortezomib treatment, MM cells become resistant to proteasome inhibition by increasing the expression of DDI2 and consequently activation of NRF1. Furthermore, we found that many MM cells became more sensitive to proteasome impairment in the context of DDI2 deficiency. Mechanistically, we demonstrate that both the protease and the HDD domains of DDI2 are required to activate NRF1. Finally, we show that partial inhibition of the DDI2-protease domain with the antiviral drug nelfinavir increased bortezomib susceptibility in treated MM cells. Altogether, these findings define the DDI2-NRF1 pathway as an essential program contributing to proteasome inhibition responses and identifying DDI2 domains that could be targets of interest in bortezomib-treated MM patients.
Keywords
Antineoplastic Agents/therapeutic use, Aspartic Acid Endopeptidases, Aspartic Acid Proteases/metabolism, Bortezomib/pharmacology, Bortezomib/therapeutic use, Cell Line, Tumor, Humans, Multiple Myeloma/drug therapy, Protease Inhibitors/pharmacology, Protease Inhibitors/therapeutic use, Proteasome Endopeptidase Complex/metabolism, Proteasome Inhibitors/pharmacology, Proteasome Inhibitors/therapeutic use
Pubmed
Web of science
Open Access
Yes
Create date
31/05/2022 13:29
Last modification date
13/07/2022 6:35
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