A Homeostatic Shift Facilitates Endoplasmic Reticulum Proteostasis through Transcriptional Integration of Proteostatic Stress Response Pathways

Mol Cell Biol. 2017 Feb 1;37(4):e00439-16. doi: 10.1128/MCB.00439-16. Print 2017 Feb 15.

Abstract

Eukaryotic cells maintain protein homeostasis through the activity of multiple basal and inducible systems, which function in concert to allow cells to adapt to a wide range of environmental conditions. Although the transcriptional programs regulating individual pathways have been studied in detail, it is not known how the different pathways are transcriptionally integrated such that a deficiency in one pathway can be compensated by a change in an auxiliary response. One such pathway that plays an essential role in many proteostasis responses is the ubiquitin-proteasome system, which functions to degrade damaged, unfolded, or short half-life proteins. Transcriptional regulation of the proteasome is mediated by the transcription factor Nrf1. Using a conditional knockout mouse model, we found that Nrf1 regulates protein homeostasis in the endoplasmic reticulum (ER) through transcriptional regulation of the ER stress sensor ATF6. In Nrf1 conditional-knockout mice, a reduction in proteasome activity is accompanied by an ATF6-dependent downregulation of the endoplasmic reticulum-associated degradation machinery, which reduces the substrate burden on the proteasome. This indicates that Nrf1 regulates a homeostatic shift through which proteostasis in the endoplasmic reticulum and cytoplasm are coregulated based on a cell's ability to degrade proteins.

Keywords: ER stress; ERAD; Nrf1; UPR; proteasome; proteostasis.

MeSH terms

  • Activating Transcription Factor 6 / metabolism
  • Animals
  • Binding Sites
  • Chromatin Immunoprecipitation
  • Down-Regulation / genetics
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum Stress / genetics*
  • Endoplasmic Reticulum-Associated Degradation / genetics*
  • Enhancer Elements, Genetic / genetics
  • Homeostasis* / genetics
  • Male
  • Membrane Proteins / metabolism
  • Mice, Knockout
  • Models, Biological
  • Nuclear Respiratory Factor 1 / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Protein Serine-Threonine Kinases / metabolism
  • Transcription, Genetic*

Substances

  • Activating Transcription Factor 6
  • Membrane Proteins
  • Nrf1 protein, mouse
  • Nuclear Respiratory Factor 1
  • Ern2 protein, mouse
  • Protein Serine-Threonine Kinases
  • Proteasome Endopeptidase Complex