Inositol-requiring enzyme (IRE) is an endoplasmic reticulum (ER) -transmembrane endonuclease that is activated in response to ER stress as part of the unfolded protein response (UPR). The chronic activation of UPR is related to the pathogenesis of many common diseases, including diabetes, cancer and neuropathology, such as Huntington's disease and Alzheimer's disease. 7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde (4µ8C) is widely used as a specific inhibitor of IRE1α ribonuclease activity (IC50 of cultured cells is 6.89µmM).

Figure 1. Protein structure of IRE.

Correlation between IRE1α kinase and IRE1α nucleic acid alcohol

IRE1α kinase is a kinase that is activated by ortho-acidification. As a bifunctional enzyme, IRE1α has always been concerned by the relationship between its kinase and nuclease. Earlier literature suggested that the phosphorylation of kinases is necessary for the activation of nucleases. However, some studies have overturned this view: Mutating the ATP binding site of the IRE1α kinase prevents the ATP from binding normally, resulting in the kinase being unable to exercise its self-pity acidification function and thus not being activated. Able to activate. This seems to indicate that the phosphate group transfer ability of IRE1α is not necessary for its nuclease activation. Other studies have suggested that inhibiting the activity of IRE1α kinase can actually activate its nuclease activity. Subsequently, it was reported that a competitive inhibitor of IRE1α kinase inhibited the autophobic acidification of IRE1α kinase and also the cleavage of nuclease substrates. Therefore, it was proposed that IRE1α nuclease activity directly depends on the autophosphorylation of its kinase.

Functions

The protein encoded by this gene is the ER of nuclear signaling 1 protein, and is a human homologue of the yeast Ire1 gene product. This protein has intrinsic kinase activity and endoribonuclease activity and is important in altering gene expression as a response to endoplasmic reticulum-based stress signals (mainly unfolded protein responses). Two alternately spliced transcriptional variants of the gene have been found to encode different isoforms.

Signaling

IRE1α has two functional enzyme domains, an endonuclease and a trans autophosphorylated kinase domain. After activation, IRE1α oligomerizes and performs unconventional RNA splicing activity, removes an intron from X-box binding protein 1 (XBP1) mRNA, and translates it into functional transcription factor XBP1s. XBP1s up-regulates endoplasmic reticulum partners and endoplasmic reticulum-associated degradation (ERAD) genes, thereby promoting the recovery of endoplasmic reticulum stress.

IRE1α kinase is a key factor in tumor growth

The proliferation capacity of tumor cells is far greater than that of normal cells. More and more studies show that benign tumors have scarce angiogenesis and slow blood vessel growth; while most malignant tumors have dense angiogenesis and rapid growth, which is to maintain tumor cell proliferation. The require of nutrient transport provides the conditions. Therefore, angiogenesis plays an important role in tumor growth, and inhibiting this effect can effectively prevent tumor growth. Vascular endothelial growth factor is indispensable in angiogenesis of normal tissues and is also a determinant of angiogenesis in tumors. The ischemic state in the tumor environment under pathological conditions will cause the lack of oxygen, sugar and nutrients in tumor tissues, which leads to the upregulation of vascular endothelial growth factor expression and tumor microenvironment.

Reference:

1. Tirasophon W; et al. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev. 1998, 12 (12): 1812–24.