Termination of the unfolded protein response is guided by ER stress-induced HAC1 mRNA nuclear retention

Nat Commun. 2022 Oct 25;13(1):6331. doi: 10.1038/s41467-022-34133-8.

Abstract

Cellular homeostasis is maintained by surveillance mechanisms that intervene at virtually every step of gene expression. In the nucleus, the yeast chromatin remodeler Isw1 holds back maturing mRNA ribonucleoparticles to prevent their untimely export, but whether this activity operates beyond quality control of mRNA biogenesis to regulate gene expression is unknown. Here, we identify the mRNA encoding the central effector of the unfolded protein response (UPR) HAC1, as an Isw1 RNA target. The direct binding of Isw1 to the 3' untranslated region of HAC1 mRNA restricts its nuclear export and is required for accurate UPR abatement. Accordingly, ISW1 inactivation sensitizes cells to endoplasmic reticulum (ER) stress while its overexpression reduces UPR induction. Our results reveal an unsuspected mechanism, in which binding of ER-stress induced Isw1 to HAC1 mRNA limits its nuclear export, providing a feedback loop that fine-tunes UPR attenuation to guarantee homeostatic adaptation to ER stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Adenosine Triphosphatases / metabolism
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • Chromatin / metabolism
  • DNA-Binding Proteins / metabolism
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum Stress
  • RNA Splicing
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Repressor Proteins / metabolism
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins* / metabolism
  • Unfolded Protein Response / genetics

Substances

  • 3' Untranslated Regions
  • Adenosine Triphosphatases
  • Basic-Leucine Zipper Transcription Factors
  • Chromatin
  • DNA-Binding Proteins
  • HAC1 protein, S cerevisiae
  • ISW1 protein, S cerevisiae
  • Repressor Proteins
  • RNA, Messenger
  • Saccharomyces cerevisiae Proteins