Multiple decay events target <i>HAC1</i> mRNA during splicing to regulate the unfolded protein response.

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 <i>HAC1</i> 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 <i>HAC1</i> 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 <i>HAC1</i> 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 <i>HAC1</i>. 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.