The aspartyl protease DDI2 drives adaptation to proteasome inhibition in multiple myeloma.
Antineoplastic Agents
/ therapeutic use
Aspartic Acid Endopeptidases
Aspartic Acid Proteases
/ metabolism
Bortezomib
/ pharmacology
Cell Line, Tumor
Humans
Multiple Myeloma
/ drug therapy
Protease Inhibitors
/ pharmacology
Proteasome Endopeptidase Complex
/ metabolism
Proteasome Inhibitors
/ pharmacology
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
19 05 2022
19 05 2022
Historique:
received:
14
12
2021
accepted:
06
05
2022
revised:
02
05
2022
entrez:
19
5
2022
pubmed:
20
5
2022
medline:
24
5
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35589686
doi: 10.1038/s41419-022-04925-3
pii: 10.1038/s41419-022-04925-3
pmc: PMC9120136
doi:
Substances chimiques
Antineoplastic Agents
0
Protease Inhibitors
0
Proteasome Inhibitors
0
Bortezomib
69G8BD63PP
Aspartic Acid Proteases
EC 3.4.-
Aspartic Acid Endopeptidases
EC 3.4.23.-
Proteasome Endopeptidase Complex
EC 3.4.25.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
475Informations de copyright
© 2022. The Author(s).
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