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Disabling the Protease DDI2 Attenuates the Transcriptional Activity of NRF1 and Potentiates Proteasome Inhibitor Cytotoxicity
- Source :
- International Journal of Molecular Sciences, Volume 21, Issue 1, International Journal of Molecular Sciences, Vol 21, Iss 1, p 327 (2020)
- Publication Year :
- 2020
- Publisher :
- Multidisciplinary Digital Publishing Institute, 2020.
-
Abstract
- Proteasome inhibition is used therapeutically to induce proteotoxic stress and trigger apoptosis in cancer cells that are highly dependent on the proteasome. As a mechanism of resistance, inhibition of the cellular proteasome induces the synthesis of new, uninhibited proteasomes to restore proteasome activity and relieve proteotoxic stress in the cell, thus evading apoptosis. This evolutionarily conserved compensatory mechanism is referred to as the proteasome-bounce back response and is orchestrated in mammalian cells by nuclear factor erythroid derived 2-related factor 1 (NRF1), a transcription factor and master regulator of proteasome subunit genes. Upon synthesis, NRF1 is cotranslationally inserted into the endoplasmic reticulum (ER), then is rapidly retrotranslocated into the cytosol and degraded by the proteasome. In contrast, during conditions of proteasome inhibition or insufficiency, NRF1 escapes degradation, is proteolytically cleaved by the aspartyl protease DNA damage inducible 1 homolog 2 (DDI2) to its active form, and enters the nucleus as an active transcription factor. Despite these insights, the cellular compartment where the proteolytic processing step occurs remains unclear. Here we further probed this pathway and found that NRF1 can be completely retrotranslocated into the cytosol where it is then cleaved and activated by DDI2. Furthermore, using a triple-negative breast cancer cell line MDA-MB-231, we investigated the therapeutic utility of attenuating DDI2 function. We found that DDI2 depletion attenuated NRF1 activation and potentiated the cytotoxic effects of the proteasome inhibitor carfilzomib. More importantly, expression of a point-mutant of DDI2 that is protease-dead recapitulated these effects. Taken together, our results provide a strong rationale for a combinational therapy that utilizes inhibition of the proteasome and the protease function of DDI2. This approach could expand the repertoire of cancer types that can be successfully treated with proteasome inhibitors in the clinic.
- Subjects :
- Transcriptional Activation
Proteasome Endopeptidase Complex
Aspartic Acid Proteases
Apoptosis
Catalysis
Article
NRF1
Inorganic Chemistry
lcsh:Chemistry
chemistry.chemical_compound
Mice
Cytosol
Cell Line, Tumor
medicine
Animals
Humans
cancer
Physical and Theoretical Chemistry
Molecular Biology
Transcription factor
lcsh:QH301-705.5
Spectroscopy
Cellular compartment
DDI2
Chemistry
Nuclear Respiratory Factor 1
proteasome inhibitor
Endoplasmic reticulum
Organic Chemistry
proteasome genes
General Medicine
Carfilzomib
Computer Science Applications
Cell biology
Protein Transport
HEK293 Cells
Proteasome
lcsh:Biology (General)
lcsh:QD1-999
Proteasome inhibitor
NIH 3T3 Cells
transcription
Oligopeptides
Proteasome Inhibitors
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 14220067
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....60bdc9f3661b48b11ddcbccf50c8acba
- Full Text :
- https://doi.org/10.3390/ijms21010327