IRE1 encodes a transmembrane protein that is involved in the unfolded protein response (5,6, 7). Heat stress, drug treatment, mutations in secretory proteins, or overexpression of wild type secretory proteins can cause unfolded proteins to accumulate in the endoplasmic reticulum (ER), triggering the unfolded protein response (UPR). Increased transcription of genes encoding soluble ER resident proteins, including chaperones, is a key feature of the UPR (see reference 7 for a review of the UPR). IRE1 is not essential under normal growth conditions, but is essential under conditions that trigger the UPR (5, 6). ire1 mutants are also inositol auxotrophs (1).

The N-terminal region of Ire1p, which contains an ER targeting sequence, senses the extent of misfolded proteins in the ER through interaction with Kar2p (4). The C-terminal half of Ire1p contains both protein kinase and site-specific endoribonuclease activities (5, 6, 2). Between these 2 halves of the protein is a functional nuclear localization sequence that is recognized by yeast importins (8). Activation of Ire1p involves release from Kar2p, oligomerization and trans-autophoshorylation, and induction of Ire1p's ribonuclease activity (9, 3, 2). The Ire1p ribonuclease performs the cleavage step in the unconventional splicing of mRNA encoding Hac1p, the transcription factor that activates gene expression in the UPR (2, 10, 7). Transcription of UPR target genes also involves the SAGA histone acetyltransferase complex; Ire1p interacts physically with SAGA components Gcn5p and Spt20p (11, 12, 7). The protein phosphatase Dcr2p is involved in downregulation of the UPR and dephosphorylates Ire1p in vitro (13). Phosphatase Ptc2p has also been shown to downregulate the UPR by dephosphorylating Ire1p (14).

The UPR in mammalian cells involves homologs of Ire1p; examples include the mouse ern1 and ern2 and human ERN1 and ERN2 gene products (15, 16, 7). The ribonuclease domain of Ire1p is similar to that of mammaliam RNase L (e.g human RNASEL) (7).

Last updated: 2007-05-14