Abstract

The unfolded protein response (UPR) monitors the protein folding capacity of the endoplasmic reticulum (ER). In all organisms analyzed to date, the UPR drives transcriptional programs that allow cells to cope with ER stress. The non-conventional splicing of Hac1 (yeasts) and XBP1 (metazoans) mRNA, encoding orthologous UPR transcription activators, is conserved and dependent on Ire1, an ER membrane-resident kinase/endoribonuclease. We found that the fission yeast Schizosaccharomyces pombe lacks both a Hac1/XBP1 ortholog and a UPR-dependent-transcriptional-program. Instead, Ire1 initiates the selective decay of a subset of ER-localized-mRNAs that is required to survive ER stress. We identified Bip1 mRNA, encoding a major ER-chaperone, as the sole mRNA cleaved upon Ire1 activation that escapes decay. Instead, truncation of its 3' UTR, including loss of its polyA tail, stabilized Bip1 mRNA, resulting in increased Bip1 translation. Thus, S. pombe uses a universally conserved stress-sensing machinery in novel ways to maintain homeostasis in the ER.DOI:http://dx.doi.org/10.7554/eLife.00048.001.

Highlights

  • Homeostatic control mechanisms are essential to life, allowing cells to balance capacity and demand of numerous physiological processes

  • unfolded protein response (UPR) induction in all eukaryotic cells analyzed to date involves the Ire1-mediated, non-conventional splicing of Hac1/XBP1 messenger RNA (mRNA)

  • Ire1 is well conserved in S. pombe, with all of the functionally important hallmarks identified in other eukaryotes, including its endoplasmic reticulum (ER) lumenal unfolded protein sensing domain and its cytosolic kinase and RNase domains

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Summary

Introduction

Homeostatic control mechanisms are essential to life, allowing cells to balance capacity and demand of numerous physiological processes. One such mechanism, the unfolded protein response (UPR), operates in all eukaryotic cells to adjust the protein folding capacity of the endoplasmic reticulum (ER) according to need. Environmental or physiological demands can lead to an imbalance between the protein folding load and the protein folding capacity in the ER lumen, resulting in an accumulation of unfolded or misfolded proteins, a condition termed ‘ER stress’ (Walter and Ron, 2011). Each sensor activates transcription factors that collaborate to drive expression of UPR target genes (Walter and Ron, 2011), including genes encoding ER-lumenal chaperones, such as BiP, an abundantly expressed Hsp family member

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