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

Takao Iwawaki,Ryoko Akai,Kenji Kohno,Michael Polymenis

doi:10.1371/journal.pone.0013052

Abstract

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 IRE1α activates X-box-binding protein 1 (XBP1) by unconventional splicing of XBP1 mRNA during ER stress. From analysis of knockout mice, both IRE1α 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 IRE1α in specific organs and tissues remains incompletely understood. Here, we analyzed the phenotype of IRE1α conditional knockout mice and found that IRE1α-deficient mice exhibit mild hypoinsulinemia, hyperglycemia, and a low-weight trend. Moreover, IRE1α 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 IRE1α and XBP1. (196 words)

Highlights

Since the majority of secretory proteins, such as antibodies, digestive enzymes, and hormones, are synthesized in the cytoplasm and are cotranslationally translocated into the lumen of the endoplasmic reticulum (ER) through a narrow channel called translocon on the ER membrane, they are initially located in the ER as unfolded and unmodified nascent polypeptides
IRE1a CKO mice exhibited mild hyperglycemia and a low-weight trend compared with control mice under free feeding conditions (Figure 1A), there was no difference in body length, amount of feed and water intake per day between IRE1a CKO and control mice (Table S1)
The measurement of blood glucose level during oral glucose tolerance test (OGTT) showed that IRE1a CKO mice have a significantly higher blood glucose level at its peak than control mice and that IRE1a CKO mice required a longer time for blood glucose level to recover than control mice (Figure 1B)

Summary

Introduction

Since the majority of secretory proteins, such as antibodies, digestive enzymes, and hormones, are synthesized in the cytoplasm and are cotranslationally translocated into the lumen of the endoplasmic reticulum (ER) through a narrow channel called translocon on the ER membrane, they are initially located in the ER as unfolded and unmodified nascent polypeptides. To adaptively respond to ER stress, the cell induces the transcriptional activation of molecules for the maturation of proteins in the ER This response is called unfolded protein response (UPR) [3]. UPR is an important cellular response for the mass production of functional secretory proteins from unfolded proteins in cells which produce them in large amounts

Methods

Results

Conclusion