IRE1α Disruption Causes Histological Abnormality of Exocrine Tissues, Increase of Blood Glucose Level, and Decrease of Serum Immunoglobulin Level

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes ER stress. As a cellular adaptive response to ER stress, unfolded protein response (UPR) activates molecules for the quality control of ER proteins. One enzyme that plays an important role in UPR is Inositol Requiring Enzyme-1 (IRE1), which is highly conserved from yeast to humans. In particular, mammalian IRE1 alpha activates X-box-binding protein 1 (XBP1) by unconventional splicing of XBP1 mRNA during ER stress. From analysis of knockout mice, both IRE1 alpha and XBP1 have been shown to be essential for development and that XBP1 is necessary for the secretory machinery of exocrine glands, plasma cell differentiation, and hepatic lipogenesis. However, the essentiality of IRE1 alpha in specific organs and tissues remains incompletely understood. Here, we analyzed the phenotype of IRE1 alpha conditional knockout mice and found that IRE1 alpha-deficient mice exhibit mild hypoinsulinemia, hyperglycemia, and a low-weight trend. Moreover, IRE1 alpha disruption causes histological abnormality of the pancreatic acinar and salivary serous tissues and decrease of serum level of immunoglobulin produced in the plasma cells, but not dysfunction of liver. Comparison of this report with previous reports regarding XBP1 conditional knockout mice might provide some clues for the discovery of the novel functions of IRE1 alpha and XBP1. (196 words)