- In eukaryotic cells, the endoplasmic reticulum (ER) is responsible for folding, modifying and trafficking a vast proportion of the proteome. When misfolded or unfolded proteins accumulate, the ER experiences stress, triggering the unfolded protein response (UPR). Among the three UPR sensors—IRE1, PERK and ATF6—IRE1 (Inositol‑requiring enzyme 1) is the most evolutionarily conserved and functionally versatile. It integrates stress sensing, transcriptional reprogramming and selective RNA degradation to restore ER homeostasis or, under severe stress, promote apoptosis.
- IRE1 is a type I transmembrane protein with a luminal stress‑sensing domain and a cytosolic region containing both kinase and endoribonuclease (RNase) activities. Under non‑stress conditions, IRE1 remains inactive through association with the ER chaperone BiP/GRP78. When misfolded proteins accumulate, BiP dissociates, allowing IRE1 to oligomerise and undergo trans‑autophosphorylation. This conformational change activates its RNase domain, initiating downstream signalling.
- The most prominent output of IRE1 activation is the unconventional splicing of XBP1 mRNA, producing the transcription factor XBP1s. XBP1s drives a broad transcriptional programme that enhances ER folding capacity, increases chaperone levels, expands lipid biosynthesis and strengthens ER‑associated degradation (ERAD). Through these actions, XBP1s supports recovery from moderate ER stress and promotes long‑term proteostasis.
- In addition to XBP1 splicing, IRE1 engages regulated IRE1‑dependent decay (RIDD), a selective RNA‑degradation pathway. RIDD targets specific mRNAs and microRNAs, reducing the influx of proteins into the ER and modulating stress‑response networks. While XBP1 splicing is primarily adaptive, RIDD can be protective or pro‑apoptotic depending on stress intensity. Under chronic or severe stress, excessive RIDD activity degrades mRNAs essential for survival, tipping the balance toward apoptosis.
- IRE1 signalling is tightly integrated with other stress‑response pathways. Crosstalk with the PERK pathway coordinates translational attenuation and antioxidant defence. Interaction with the ATF6 pathway ensures balanced induction of chaperones and ERAD components. IRE1 also interfaces with the proteostasis network, autophagy and the oxidative stress response, forming a unified system that preserves cellular integrity under stress.
- Beyond the ER, IRE1 influences mitochondrial function, lipid metabolism and inflammatory signalling. Its cytosolic domain interacts with TRAF2, linking ER stress to JNK activation and apoptosis. This duality—adaptive under moderate stress, apoptotic under severe stress—makes IRE1 a central decision‑making node in cellular stress biology.
- Dysregulation of IRE1 contributes to numerous diseases. Hyperactivation of IRE1–XBP1 signalling supports tumour growth by enabling cancer cells to tolerate high secretory demand and proteotoxic stress. In neurodegenerative diseases, chronic ER stress and maladaptive RIDD activity contribute to neuronal dysfunction. In metabolic disorders such as diabetes, impaired IRE1 signalling disrupts insulin production and lipid homeostasis.
- In summary, IRE1 is the master ER stress sensor that integrates protein‑folding surveillance with transcriptional reprogramming and RNA degradation. Through XBP1 splicing, RIDD activity and extensive crosstalk with other stress pathways, IRE1 orchestrates adaptive responses that restore proteostasis or, when recovery fails, initiates apoptosis. Its central role in ER biology, metabolism and disease makes IRE1 a key focus of modern cell‑stress research.
