Proteasomal degradation is transcriptionally controlled by TCF11 via an ERAD-dependent feedback loop

Mol Cell. 2010 Oct 8;40(1):147-58. doi: 10.1016/j.molcel.2010.09.012.


Coordinated regulation of the ubiquitin-proteasome system (UPS) is crucial for the cell to adjust its protein degradation capacity to changing proteolytic requirements. We have shown previously that mammalian cells upregulate proteasome gene expression in response to proteasome inhibition. Here, we report the identification of the transcription factor TCF11 (long isoform of Nrf1) as a key regulator for 26S proteasome formation in human cells to compensate for reduced proteolytic activity. Under noninducing conditions, TCF11 resides in the endoplasmic reticulum (ER) membrane. There, TCF11 is targeted to ER-associated protein degradation requiring the E3 ubiquitin ligase HRD1 and the AAA ATPase p97. Proteasome inhibitors trigger the accumulation of oxidant-damaged proteins and promote the nuclear translocation of TCF11 from the ER, permitting activation of proteasome gene expression by binding to antioxidant response elements in their promoter regions. Thus, we uncovered the transcriptional control loop regulating human proteasome-dependent protein degradation to counteract proteotoxic stress caused by proteasome inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities
  • Active Transport, Cell Nucleus
  • Adenosine Triphosphatases / metabolism
  • Amino Acid Sequence
  • Antioxidants / metabolism
  • Cell Line
  • Endoplasmic Reticulum / metabolism*
  • Endothelial Cells / drug effects
  • Endothelial Cells / enzymology*
  • Feedback, Physiological
  • Gene Expression Regulation
  • Homeostasis
  • Humans
  • Molecular Sequence Data
  • NF-E2-Related Factor 1 / genetics
  • NF-E2-Related Factor 1 / metabolism*
  • Nuclear Proteins / metabolism
  • Oxidative Stress
  • Protease Inhibitors / pharmacology
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors
  • Protein Processing, Post-Translational* / drug effects
  • Protein Processing, Post-Translational* / genetics
  • RNA Interference
  • RNA, Messenger / metabolism
  • Response Elements
  • Transcription, Genetic* / drug effects
  • Transfection
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination


  • Antioxidants
  • NF-E2-Related Factor 1
  • NFE2L1 protein, human
  • Nuclear Proteins
  • Protease Inhibitors
  • Proteasome Inhibitors
  • RNA, Messenger
  • Ubiquitin
  • SYVN1 protein, human
  • Ubiquitin-Protein Ligases
  • PSMB4 protein, human
  • PSMB6 protein, human
  • PSMC4 protein, human
  • Proteasome Endopeptidase Complex
  • ATP dependent 26S protease
  • Adenosine Triphosphatases
  • p97 ATPase
  • ATPases Associated with Diverse Cellular Activities