ER-trafficking triggers NRF1 ubiquitination to promote its proteolytic activation.

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.

The protease DDI2 regulates NRF1 activation in response to cadmium toxicity.

DNA-damage inducible 1 homolog 2 (DDI2) is a protease that activates the transcription factor NRF1. Cellular models have shown that this pathway contributes to cell-stress adaptation, for example, on proteasome inhibition. However, DDI2 physiological function is unknown.

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

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.