Negative feedback by IRE1β optimizes mucin production in goblet cells

Akio Tsuru, Naoko Fujimoto, Satsuki Takahashi, Michiko Saito, Daisuke Nakamura, Megumi Iwano, Takao Iwawaki, Hiroshi Kadokura, David Ron, Kenji Kohno

Research output: Contribution to journalArticlepeer-review

97 Citations (Scopus)

Abstract

In mammals, the prototypical endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1 (IRE1) has diverged into two paralogs. IRE1α is broadly expressed and mediates the unconventional splicing of X-box binding protein 1 (XBP1) mRNA during ER stress. By contrast, IRE1β is expressed selectively in the digestive tract, and its function remains unclear. Here, we report that IRE1β plays a distinctive role in mucin-secreting goblet cells. In IRE1β-/- mice, aberrant mucin 2 (MUC2) accumulated in the ER of goblet cells, accompanied by ER distension and elevated ER stress signaling such as increased XBP1 mRNA splicing. In contrast, conditional IRE1α-/- mice showed no such ER distension but a marked decrease in spliced XBP1 mRNA. mRNA stability assay revealed that MUC2 mRNA was greatly stabilized in IRE1β-/- mice. These findings suggest that in goblet cells, IRE1β, but not IRE1α, promotes efficient protein folding and secretion in the ER by optimizing the level of mRNA encoding their major secretory product, MUC2.

Original languageEnglish
Pages (from-to)2864-2869
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number8
DOIs
Publication statusPublished - 2013 Feb 19
Externally publishedYes

Keywords

  • Inflammatory bowel disease
  • Unfolded protein response

ASJC Scopus subject areas

  • General

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