The fail-safe mechanism of post-transcriptional silencing of unspliced <i>HAC1</i> mRNA.

Abstract

<i>HAC1</i> encodes a transcription factor that is the central effector of the unfolded protein response (UPR) in budding yeast. When the UPR is inactive, <i>HAC1</i> mRNA is stored as an unspliced isoform in the cytoplasm and no Hac1 protein is detectable. Intron removal is both necessary and sufficient to relieve the post-transcriptional silencing of <i>HAC1</i> mRNA, yet the precise mechanism by which the intron prevents Hac1 protein accumulation has remained elusive. Here, we show that a combination of inhibited translation initiation and accelerated protein degradation-both dependent on the intron-prevents the accumulation of Hac1 protein when the UPR is inactive. Functionally, both components of this fail-safe silencing mechanism are required to prevent ectopic production of Hac1 protein and concomitant activation of the UPR. Our results provide a mechanistic understanding of <i>HAC1</i> regulation and reveal a novel strategy for complete post-transcriptional silencing of a cytoplasmic mRNA.