Figure 5.

Feedback control of proteasome levels in yeast and mammals. (A) In S. cerevisiae, transcription factor Rpn4 controls the level of expression of proteasome subunits. Rpn4 is stabilized under specific proteotoxic stresses, inducing the transcription of proteasomal subunit genes regulated by proteasome-associated control (PACE) elements. (B) In mammals, NRF1 is the key transcriptional regulator of proteasome subunit genes. A resident of the endoplasmic reticulum (ER), NRF1 is ubiquitinated by HRD1 and retrotranslocated by p97. NRF1 protein can then be degraded via the proteasome as an ERAD substrate or cleaved endoproteolytically by the protease DDI2, resulting in its liberation from the ER membrane. The cleaved version of NRF1 is translocated to the nucleus where it binds ARE elements and induces the transcription of genes for proteasome subunits. The nuclear form of NRF1 is also rapidly degraded by the proteasome (see main text).