A homeostatic shift facilitates endoplasmic reticulum proteostasis through transcriptional integration of proteostatic stress response pathways

Liam Baird, Tadayuki Tsujita, Eri H. Kobayashi, Ryo Funayama, Takeshi Nagashima, Keiko Nakayama, Masayuki Yamamoto

研究成果: Article査読

30 被引用数 (Scopus)

抄録

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.

本文言語English
論文番号e00439
ジャーナルMolecular and cellular biology
37
4
DOI
出版ステータスPublished - 2017

ASJC Scopus subject areas

  • 分子生物学
  • 細胞生物学

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