Negative feedback by IRE1β optimizes mucin production in goblet cells

Area of Science:

• Cell Biology
• Molecular Biology
• Gastroenterology

Background:

• The endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1 (IRE1) has two paralogs in mammals: IRE1α and IRE1β.
• IRE1α is widely expressed and splices X-box binding protein 1 (XBP1) mRNA during ER stress.
• IRE1β is selectively expressed in the digestive tract, with its function largely unknown.

Purpose of the Study:

• To investigate the specific function of IRE1β in mucin-secreting goblet cells.
• To elucidate the role of IRE1β in regulating mucin 2 (MUC2) protein processing and secretion.
• To compare the functions of IRE1β and IRE1α in the context of ER stress and protein homeostasis.

Main Methods:

• Generated and analyzed IRE1β knockout (IRE1β(-/-)) mice.
• Generated and analyzed conditional IRE1α knockout (IRE1α(-/-)) mice.
• Performed mRNA stability assays to assess MUC2 mRNA levels.

Main Results:

• IRE1β(-/-) mice exhibited MUC2 accumulation in the ER of goblet cells, ER distension, and increased XBP1 mRNA splicing.
• Conditional IRE1α(-/-) mice did not show ER distension but had reduced spliced XBP1 mRNA.
• mRNA stability assays indicated significantly increased MUC2 mRNA stability in IRE1β(-/-) mice.

Conclusions:

• IRE1β, unlike IRE1α, plays a critical role in promoting efficient protein folding and secretion in goblet cells.
• IRE1β optimizes the levels of MUC2 mRNA, the primary secretory product in these cells.
• These findings highlight a specialized function of IRE1β in maintaining ER homeostasis within the digestive tract.