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Regulating ER protein homeostasis by differentially processing mRNAs


The endoplasmic reticulum (ER) protein folding capacity is balanced with the protein folding burden to prevent accumulation of un- or misfolded proteins. The ER-membrane resident kinase/RNase Ire1 maintains ER protein homeostasis by initiating two distinct mRNA processing programs. First, in both metazoans and Saccharomyces cerevisiae, Ire1 catalyzes the non-conventional cytoplasmic mRNA splicing of XBP1 (metazoans) or HAC1 (S. cerevisiae)—thereby initiating a transcriptional response that increases the ER folding capacity. Second, in metazoans and Schizosaccharomyces pombe, Ire1 selectively degrades ER-localized mRNAs—thereby post-transcriptionally reducing the ER’s protein folding burden. Thus, Ire1 orthologs in S. cerevisiae and S. pombe are specialized to only one of the two functional outputs, while Ire1 in metazoans can perform both. Here, we show that the respective Ire1 orthologs have become specialized for their functional outputs by divergence of their RNase specificities. In addition, RNA structural features separate the splicing substrates from the decay substrates. Using these insights, we de novo engineered non-conventional mRNA splicing in S. pombe, which confers S. pombe with both Ire1 functional outputs.

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