Author response: The aspartyl protease DDI2 activates Nrf1 to compensate for proteasome dysfunction

The proteasome is a machine that destroys unnecessary or damaged proteins inside cells. This role of the proteasome is essential for cell survival, and so when the proteasome is inhibited, cells produce new proteasomes to compensate. Upon proteasome inhibition, a protein called Nrf1 is activated and executes this “bounce-back” response. Some cancer treatments aim to kill cancer cells by inhibiting proteasomes, but these treatments may be unsuccessful if the bounce-back response is not also prevented. Therefore, understanding how Nrf1 is activated is an important issue. Nrf1 is produced at a structure called the endoplasmic reticulum in cells and is continually destroyed by the proteasome. On the other hand, when proteasomes are inhibited, Nrf1 accumulates and is cleaved into an active form, which moves to the cell nucleus to start producing proteasomes. However, it was not known which molecule cleaves Nrf1. Koizumi et al. set out to discover this molecule by screening the genetic material of human cells, and identified a gene that encodes a protease (an enzyme that cleaves other proteins) called DDI2. The loss of DDI2 from cells prevented Nrf1 from being cleaved and entering the nucleus, resulting in low levels of proteasome production. Further experiments showed that a mutant form of DDI2 that lacked protease activity was unable to cleave Nrf1, confirming DDI2’s role in activating Nrf1. Deleting DDI2 from cells does not completely prevent the cleavage of Nrf1, and so some other cleaving enzyme might exist; the identity of this enzyme remains to be discovered. Future work is also needed to establish exactly how DDI2 cleaves Nrf1. This could help to develop a DDI2 inhibitor for cancer treatment that could be used in combination with existing proteasome inhibitors.