FIG. 8.

Proposed TCF11/Nrf1-dependent cellular adaptive mechanism. (A) Under unstressed conditions, protein synthesis and protein degradation/recycling are balanced, maintaining protein homeostasis. TCF11/Nrf1 resides in the ER membrane and is degraded by the ERAD pathway. (B) Cytotoxic stress leads to increased levels of oxidative damaged or misfolded proteins and therefore requires adaptation of the protein homeostasis for efficient clearance. To effectuate the increase in the proteolytic requirement, TCF11/Nrf1 is retrotranslocated and transferred to the nucleus. There, it binds to the ARE region of the promoter of proteasome subunit genes, thereby inducing their expression. The increased expression of the proteasome subunits finally results in an upregulation of newly synthesized active proteasome complexes, increasing the degradation capacity of the cell. ARE, antioxidant response elements.