The protease DDI2 regulates NRF1 activation in response to cadmium toxicity

Early recovery of proteasome activity in cells pulse-treated with proteasome inhibitors is independent of DDI2

“…Although we confirmed this observation in HAP1 cells (not shown), the present findings raise a possibility that DDI2 desensitizes cells to PI by a different mechanism. Activation of non-proteasomal Nrf1-dependent oxidative stress response genes ( Ribeiro et al, 2022 ; Kim et al, 2016 ) may help overcome the deleterious consequences of PI-induced overproduction of reactive oxygen species (ROS) ( Lipchick et al, 2016 ). Alternatively, the ability of DDI2 to bind and participate in the degradation of large ubiquitin conjugates ( Dirac-Svejstrup et al, 2020 ; Collins et al, 2022 ) may help alleviate the stress associated with proteasome inhibition.…”

Early recovery of proteasome activity in cells pulse-treated with proteasome inhibitors is independent of DDI2

“…Although we confirmed this observation in HAP1 cells (not shown), the present findings raise a possibility that DDI2 desensitizes cells to PI by a different mechanism. Activation of non-proteasomal Nrf1-dependent oxidative stress response genes [32, 33] may help overcome the deleterious consequences of PI-induced overproduction of reactive oxygen species (ROS) [34]. Alternatively, the ability of DDI2 to bind and participate in the degradation of large ubiquitin conjugates [31, 35] may help alleviate the stress associated with proteasome inhibition.…”

Unravelling the role of NFE2L1 in stress responses and related diseases

“…In addition, NFE2L1 also participate in metal-based chemotherapy. Several metal compounds can disrupt UPS and interfere with proteasome function [ 171 ], thus NFE2L1 can mediate detoxification of metal exposure by maintaining proteostasis to protect cells from patulin cytotoxicity [ 172 ], and cadmium toxicity [ 173 ]. Persistent toxic stress can induce several cancers, for instance, prolonged arsenic exposure is highly linked to lung cancer development.…”

“…Interestingly, NFE2L1 can regulate metallothionein (MT) expression, which is positively associated with the chemoresistance of metal-based medications in cancers, such as cisplatin. This indicates the feasibility of DDI2-NFE2L1-MT axis inhibition in potentiating metal-based chemotherapy [ [155] , [173] , [174] ]. Although post-translational modification of NFE2L1 can improve the sensitivity of chemotherapeutic agents, the upstream mechanism of NFE2L1 activation by PIs is still unclear, so it is important to clarify the upstream mechanism of the proteasomal “bounce-back” effect to guide the application of PIs in solid tumors.…”