Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States; Howard Hughes Medical Institute, San Francisco, United States
Voytek Okreglak
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States; Howard Hughes Medical Institute, San Francisco, United States
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States; Howard Hughes Medical Institute, San Francisco, United States
Philipp Kimmig
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States; Howard Hughes Medical Institute, San Francisco, United States
Meghan Zubradt
Howard Hughes Medical Institute, San Francisco, United States; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
Howard Hughes Medical Institute, San Francisco, United States; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States; Howard Hughes Medical Institute, San Francisco, United States
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 through two fundamentally distinct processes. First, Ire1 can initiate a transcriptional response through a non-conventional mRNA splicing reaction to increase the ER folding capacity. Second, Ire1 can decrease the ER folding burden through selective mRNA decay. In Saccharomyces cerevisiae and Schizosaccharomyces pombe, the two Ire1 functions have been evolutionarily separated. 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 engineered an S. pombe Ire1 cleavage substrate into a splicing substrate, which confers S. pombe with both Ire1 functional outputs.
