Multiple decay events target HAC1 mRNA during splicing to regulate the unfolded protein response

Elife. 2019 Mar 15;8:e42262. doi: 10.7554/eLife.42262.

Abstract

In the unfolded protein response (UPR), stress in the endoplasmic reticulum (ER) activates a large transcriptional program to increase ER folding capacity. During the budding yeast UPR, Ire1 excises an intron from the HAC1 mRNA and the exon products of cleavage are ligated, and the translated protein induces hundreds of stress-response genes. Using cells with mutations in RNA repair and decay enzymes, we show that phosphorylation of two different HAC1 splicing intermediates is required for their degradation by the 5'→3' exonuclease Xrn1 to enact opposing effects on the UPR. We also found that ligated but 2'-phosphorylated HAC1 mRNA is cleaved, yielding a decay intermediate with both 5'- and 2'-phosphates at its 5'-end that inhibit 5'→3' decay and suggesting that Ire1 degrades incompletely processed HAC1. These decay events expand the scope of RNA-based regulation in the budding yeast UPR and have implications for the control of the metazoan UPR.

Keywords: RNA decay; RNA repair; S. cerevisiae; chromosomes; gene expression; unfolded protein response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic-Leucine Zipper Transcription Factors / biosynthesis*
  • Exoribonucleases / metabolism
  • Gene Expression Regulation, Fungal*
  • Membrane Glycoproteins / metabolism
  • Protein Serine-Threonine Kinases / metabolism
  • RNA Splicing*
  • RNA Stability*
  • RNA, Messenger / metabolism*
  • Repressor Proteins / biosynthesis*
  • Saccharomyces cerevisiae / physiology*
  • Saccharomyces cerevisiae Proteins / biosynthesis*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Unfolded Protein Response*

Substances

  • Basic-Leucine Zipper Transcription Factors
  • HAC1 protein, S cerevisiae
  • Membrane Glycoproteins
  • RNA, Messenger
  • Repressor Proteins
  • Saccharomyces cerevisiae Proteins
  • IRE1 protein, S cerevisiae
  • Protein Serine-Threonine Kinases
  • Exoribonucleases
  • XRN1 protein, S cerevisiae