A role for presenilin-1 in nuclear accumulation of Ire1 fragments and induction of the mammalian unfolded protein response

The unfolded protein response (UPR) mediates signaling from the endoplasmic reticulum to the nucleus. In yeast, a key regulatory step in the UPR is th e spliceosome-independent splicing of HAC1 mRNA encoding a UPR-specific tra nscription factor, which is initiated by the transmembrane kinase/endoribon uclease Ire1. We show that yeast HAC1 mRNA is correctly spliced in mammalia n cells upon UPR induction and that mammalian Ire1 can precisely cleave bot h splice junctions. Surprisingly, UPR induction leads to proteolytic cleava ge of Ire1, releasing fragments containing the kinase and nuclease domains that accumulate in the nucleus. Nuclear localization and UPR induction are reduced in presenilin-1 knockout cells. These results suggest that the sali ent features of the UPR are conserved among eukaryotic cells and that prese nilin-1 controls Ire1 proteolysis in mammalian cells.