What is the inositol-requiring enzyme 1 (IRE1)?

Inositol-requiring enzyme 1 (IRE1) is an endoplasmic reticulum (ER) transmembrane protein that plays a crucial role in the unfolded protein response (UPR) pathway. It is one of the three primary sensors of ER stress, along with protein kinase RNA-like ER kinase (PERK) and activating transcription factor 6 (ATF6).

IRE1 is composed of an ER luminal domain, a single transmembrane domain, and a cytoplasmic domain with kinase and endoribonuclease (RNase) activities. There are two isoforms of IRE1: IRE1α (ERN1) and IRE1β (ERN2). IRE1α is the more extensively studied isoform and is ubiquitously expressed in various tissues, while IRE1β has a more limited expression pattern.

During normal conditions, IRE1α is maintained in an inactive state through interaction with the ER chaperone protein called BiP/Grp78. However, when the ER becomes stressed due to the accumulation of unfolded or misfolded proteins, BiP/Grp78 dissociates from IRE1α, leading to its activation.

Activated IRE1α undergoes dimerization and autophosphorylation, which activates its kinase domain. The activated kinase domain of IRE1α then phosphorylates itself and other downstream targets. One of its key downstream targets is the X-box binding protein 1 (XBP1) mRNA.

IRE1α possesses an endoribonuclease (RNase) activity that cleaves a 26-nucleotide intron from the unspliced XBP1 mRNA, resulting in the production of spliced XBP1 mRNA. This spliced XBP1 mRNA is then translated into a transcription factor known as spliced XBP1 protein. The spliced XBP1 protein translocates to the nucleus and activates the transcription of genes involved in ER-associated protein degradation (ERAD), protein folding, and other UPR-related processes. These genes help alleviate ER stress and restore ER homeostasis.

In addition to its role in XBP1 splicing, IRE1α also possesses non-canonical RNase activities involved in the degradation of other mRNAs, which is thought to be important for regulating ER stress and UPR signaling.

IRE1α is a central component of the UPR pathway and plays a vital role in coordinating the cellular response to ER stress by promoting adaptation and survival or initiating apoptosis if ER stress is severe and prolonged.