Mechanism of Nrf1 activation. Upon completion of synthesis, Nrf1 is rapidly directed into the retrotranslocation pathway (1). p97 extracts Nrf1 from the ER, and it is then fed to the proteasome (2). Because of the tight coupling between synthesis, retrotranslocation, and degradation, there is very little accumulation of Nrf1 at steady-state. In cells that are deficient in proteasome activity (3), retrotranslocation and degradation of Nrf1 become kinetically uncoupled. Accumulation of Nrf1 on the cytosolic side of the membrane renders it susceptible to cleavage by an unknown protease (5), which releases a soluble 110 kDa fragment that translocates to the nucleus and activates transcription of genes that encode proteasome subunits. PSM: proteasome components.