Nuclear mRNA degradation tunes the gain of the unfolded protein response in Saccharomyces cerevisiae

Nucleic Acids Res. 2018 Feb 16;46(3):1139-1156. doi: 10.1093/nar/gkx1160.

Abstract

Unfolded protein response (UPR) is triggered by the accumulation of unfolded proteins in the endoplasmic reticulum (ER), which is accomplished by a dramatic induction of genes encoding ER chaperones. Activation of these genes involves their rapid transcription by Hac1p, encoded by the HAC1 precursor transcript harboring an intron and a bipartite element (3'-BE) in the 3'-UTR. ER stress facilitates intracellular targeting and recruitment of HAC1 pre-mRNA to Ire1p foci (requiring 3'-BE), leading to its non-spliceosomal splicing mediated by Ire1p/Rlg1p. A critical concentration of the pre-HAC1 harboring a functional 3'-BE element is governed by its 3'→5' decay by the nuclear exosome/DRN. In the absence of stress, pre-HAC1 mRNA undergoes a rapid and kinetic 3'→5' decay leading to a precursor pool, the majority of which lack the BE element. Stress, in contrast, causes a diminished decay, thus resulting in the production of a population with an increased abundance of pre-HAC1 mRNA carrying an intact BE, which facilitates its more efficient recruitment to Ire1p foci. This mechanism plays a crucial role in the timely activation of UPR and its prompt attenuation following the accomplishment of homeostasis. Thus, a kinetic mRNA decay provides a novel paradigm for mRNA targeting and regulation of gene expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Basic-Leucine Zipper Transcription Factors / genetics*
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • Cell Nucleus / metabolism
  • Gene Expression Regulation, Fungal*
  • Kinetics
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / metabolism
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • RNA Precursors / genetics*
  • RNA Precursors / metabolism
  • RNA Splicing
  • RNA Stability
  • RNA, Fungal / genetics
  • RNA, Fungal / metabolism
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Transcription, Genetic
  • Unfolded Protein Response*

Substances

  • 3' Untranslated Regions
  • Basic-Leucine Zipper Transcription Factors
  • HAC1 protein, S cerevisiae
  • Membrane Glycoproteins
  • RNA Precursors
  • RNA, Fungal
  • Repressor Proteins
  • Saccharomyces cerevisiae Proteins
  • IRE1 protein, S cerevisiae
  • Protein Serine-Threonine Kinases