title: A Homeostatic Shift Facilitates Endoplasmic Reticulum Proteostasis through Transcriptional Integration of Proteostatic Stress Response Pathways.
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.
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan liambaird@med.tohoku.ac.jp masiyamamoto@med.tohoku.ac.jp.
authors.forename: Liam
authors.initials: L
authors.lastname: Baird
authors.affiliation: Laboratory of Biochemistry, Department of Applied Biochemistry and Food Science, Faculty of Agriculture, Saga University, Saga, Japan.
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Tsujita
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Eri H
authors.initials: EH
authors.lastname: Kobayashi
authors.affiliation: Division of Cell Proliferation, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Funayama
authors.affiliation: Division of Cell Proliferation, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagashima
authors.affiliation: Division of Cell Proliferation, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakayama
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan liambaird@med.tohoku.ac.jp masiyamamoto@med.tohoku.ac.jp.|Tohoku Medical Megabank Organization, Sendai, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D047369:Chromatin Immunoprecipitation; D015536:Down-Regulation / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D060746:Endoplasmic Reticulum-Associated Degradation / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D006706:Homeostasis / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D018345:Mice, Knockout; D008954:Models, Biological; D051266:Nuclear Respiratory Factor 1 / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D051702:Activating Transcription Factor 6; D008565:Membrane Proteins; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; C486556:Ern2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex
keywords: ER stress; ERAD; Nrf1; UPR; proteasome; proteostasis