Regulating ER Protein Folding Homeostasis By Distinctively Processing mRNAs

The endoplasmic reticulum (ER) is the major folding compartment for most secretory and plasma membrane proteins in the cell. A conserved signaling pathway, the unfolded protein response, senses and modulates the folding capacity of the ER. To maintain ER protein folding homeostasis under ER stress conditions, the ER membrane embedded sensor, Ire1, initiates two distinct mRNA processing programs through its cytoplasmic kinase/RNase domains. First, in both metazoans and S. cerevisiae , Ire1 catalyzes the unconventional 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 S. pombe , Ire1 selectively degrades ER‐localized mRNAs—thereby post‐transcriptionally reducing the ER's protein folding burden through regulated Ire1‐dependent mRNA decay. Thus, Ire1 homologs in S. cerevisiae and S. pombe are specialized to only one of the two functional outputs, while Ire1 in metazoans can perform both. We found that S. cerevisiae and S. pombe Ire1 have distinct RNase specificity, which determine their functional outputs. In addition, we nailed down to three Ire1 residues, which regulate Ire1 RNase specificity by regulating its dimer‐packing. Finally, by applying our new findings, we successfully reconstituted unconventional mRNA splicing in S. pombe cells. Therefore, we engineered S. pombe into a metazoan‐like Ire1 system, where unconventional mRNA splicing and selective mRNA decay co‐exist. Our results provide new insights into a mechanistic understanding of Ire1 function and its interplay with RNA substrates. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .