"The UniProt accession **P32361** corresponds to **budding yeast (*Saccharomyces cerevisiae* S288c) Ire1/Ern1 (YHR079C)**, an **ER-resident single-pass (type I) transmembrane stress sensor** with a **cytosolic serine/threonine kinase domain and an endoribonuclease (RNase) domain** that initiates the yeast unfolded protein response (UPR) by **splicing HAC1 mRNA**."

"**Reaction:** Ire1's RNase performs **site-specific endonucleolytic cleavage** of **HAC1u mRNA** at both the **5′ and 3′ splice junctions**, thereby removing an inhibitory intron and initiating spliceosome-independent splicing."

"Point mutations in critical guanosine residues at splice junctions (e.g., **G885C at the 5′ junction**) selectively block cleavage at that junction in vivo and in vitro, demonstrating that **Ire1 recognizes specific splice-junction determinants** in HAC1... omission of ATP abolishes cleavage, while **ADP** or **AMP-PNP** can substitute; **GTP cannot**."

"Sidrauski & Walter reconstituted the full splicing reaction in vitro with **purified Ire1 fragment + purified tRNA ligase**, showing that these components are sufficient to produce correctly spliced HAC1."

"Ire1 has a **Ser/Thr kinase domain** that undergoes **trans-autophosphorylation** upon oligomerization, which is coupled to RNase activation in current models of UPR induction."

"Beyond enabling activation, kinase function is implicated in **attenuation/homeostatic shutdown**: mechanistic syntheses report kinase-dependent processes contributing to the disassembly of Ire1 oligomers and termination of signaling."

"Ire1 is an **ER membrane protein** with a luminal stress-sensing domain and cytosolic kinase/RNase module; it forms **puncta/clusters** on the ER membrane during stress, consistent with its role as a spatially organized RNA-processing hub... HAC1u mRNA is recruited to Ire1 puncta/clusters for splicing during ER stress."

"Under non-stress conditions Kar2/BiP binding keeps Ire1 in a less self-associated state; ER stress promotes Kar2 dissociation and Ire1 self-association/activation... Ire1 activation can involve direct engagement of unfolded proteins via its luminal domain, which promotes oligomerization and signaling."

"Recent yeast-focused syntheses emphasize that Ire1 can be activated not only by unfolded proteins but also by **lipid bilayer stress**, sensed via Ire1's transmembrane/amphipathic features. LBS tends to promote **dimeric** rather than large oligomeric Ire1 assemblies and can elicit **weaker RNase output** and a milder UPR."

"Authoritative 2023–2024 reviews state that **regulated Ire1-dependent decay (RIDD)**—Ire1 RNase cleavage of additional ER-associated mRNAs—is **absent (or not convincingly supported) in *S. cerevisiae***, in contrast to other organisms such as *S. pombe* and metazoans. The yeast literature summarized indicates that **HAC1 is effectively the predominant (possibly sole) physiologically relevant Ire1 RNase substrate** in budding yeast."

"Yeast UPR is effectively a single-sensor, single-transcription-factor architecture (Ire1→Hac1), which enables unusually clean genetic epistasis and mechanistic dissection."

"A 2023 bioRxiv preprint proposes that **MAPK Slt2** enhances both **HAC1 mRNA splicing and translation**, contributing to adaptation under ER stress."