High impact information on IRE1

• IRE1 encodes a transmembrane serine/threonine kinase that we propose transmits the unfolded protein signal across the ER or inner nuclear membrane [1].
• Moreover, IRE1 is essential for cell viability under stress conditions that cause unfolded proteins to accumulate in the ER [1].
• IRE1 is also required for inositol prototrophy, suggesting that the induction of ER resident proteins is coupled to the biogenesis of new ER membrane [1].
• Several yeast mutants defective in this pathway map to the ERN1 gene, which protects cells from lethal consequences of stress by signaling for increased expression of BiP and other ER proteins [2].
• ERN1 encodes a 1115 amino acid transmembrane protein (Ern1p) whose glycosylated N-terminal portion is located inside microsomes and whose cytoplasmic C-terminal portion carries an essential protein kinase activity [2].

Biological context of IRE1

• Here, we demonstrate that in addition to this well-understood ER stress signalling pathway, a second, IRE1, HAC1 and UPRE-independent mechanism for transcriptional activation upon ER stress, exists in yeast [3].
• We have characterized a yeast gene, IRE2, which was isolated as a suppressor gene that complements the inositol auxotrophic phenotype of the ire1 mutation [4].
• The mechanisms by which mammalian IRE1 activates gene expression have not been completely characterized and mammalian HAC1 homologues have not been identified [5].
• The amino acid sequences of the amino-terminal ER luminal domains (NLDs) from IRE1 and PERK display limited homology and have diverged among species [6].
• These results demonstrate that ER stress-induced dimerization of the NLD is sufficient for IRE1 and PERK activation and is conserved through evolution [6].

Anatomical context of IRE1

• IRE1 and efferent signaling from the endoplasmic reticulum [5].
• IRE1 is present in all eukaryotic cells and signals the unfolded protein response through its kinase and endoribonuclease activities [6].

Associations of IRE1 with chemical compounds

• The Saccharomyces cerevisiae IRE1 gene, encoding a putative receptor-type protein kinase, is known to be required for inositol prototrophy and for the induction of a chaperon molecule, BiP, encoded by KAR2, under stress conditions such as tunicamycin addition [4].
• These results suggest that the karmellae-dependent death of certain ire1 strains may simply reflect their inability to grow on galactose [7].
• Overexpression of ire1 in a T. reesei strain that expresses a foreign protein (laccase 1 from Phlebia radiata), results in up-regulation of the UPR pathway, as indicated by the increased expression levels of the known UPR target genes bip1 and pdi1 [8].
• Although substitution of Pro for Ser103 (S103P) in the luminal domain of full-length Ire1 caused neither BiP dissociation nor a change in self-association, the substitution in combination with the core mutation resulted in constitutive activation [9].

Physical interactions of IRE1

• We speculate that recognition of unfolded proteins is based on their competition with Ire1 for binding with BiP/Kar2 [10].

Regulatory relationships of IRE1

• In the yeast UPR signaling pathway, the ER-located transmembrane protein Ire1 promotes splicing of the HAC1 premRNA (HAC1(u)) to produce the translatable transcription factor mRNA (HAC1i) [11].
• Genetic evidence for a role of BiP/Kar2 that regulates Ire1 in response to accumulation of unfolded proteins [10].
• Ire1 regulated XBP1 mRNA splicing is essential for the unfolded protein response (UPR) in Drosophila melanogaster [12].

Other interactions of IRE1

• We conclude that IRE1 and ERD2 together maintain normal concentrations of resident proteins within the ER [13].
• In an effort to identify genes that positively regulate Sec12p, we isolated IRE1 as a novel multicopy suppressor of the temperature-sensitive sec12-4 mutant [14].
• We sought to determine whether the karmellae-dependent death of ire1 mutants was due to karmellae assembly or to increased levels of HMG-CoA reductase activity [7].
• The ire1 and ptc2 genes involved in the unfolded protein response pathway in the filamentous fungus Trichoderma reesei [8].

Analytical, diagnostic and therapeutic context of IRE1

• The unfolded protein response entered the mechanistic realm with the discovery of IRE1 as the key signal transducer in yeast [15].
• Western blotting confirmed that Kar2p levels were increased to the same extent in the ire1 disruptant and in the non-disruptant strain [16].

References