When the AGR2 protein is missing or reduced in cells lining the intestine and stomach, a cellular stress response in the endoplasmic reticulum increases, marked by higher levels of the BiP protein,...
Mechanism
Synthesis from 1 study
When AGR2 doesn't work right, the cell's protein-folding system gets clogged with broken mucus proteins and can't recover, no matter how much more of the broken AGR2 it makes. This overload damages the cell, kills the mucus-producing cells, and leaves the gut unprotected.
Most probable mechanism
When AGR2 is broken or missing, cells in the gut and stomach can't properly fold a key mucus protein, causing it to pile up inside the cell's protein-folding factory. This overload overwhelms the factory's ability to handle stress, and even if the cell tries to make more of the broken AGR2, it still can't fix the problem. As a result, the factory gets damaged, the cells start to die, and the protective mucus layer breaks down.
AGR2 protein fails to bind and assist in the proper folding of the MUC2 mucin precursor in the endoplasmic reticulum
Misfolded MUC2 accumulates in the endoplasmic reticulum, exceeding its folding capacity and disrupting proteostasis
Endoplasmic reticulum stress response is activated, marked by increased BiP expression, but cannot be resolved due to AGR2 dysfunction
AGR2 deficiency directly impairs the cell's ability to mitigate endoplasmic reticulum stress, even in the absence of mucin production
Persistent endoplasmic reticulum stress triggers apoptosis in epithelial cells, particularly mucus-producing goblet cells
Upregulated expression of mutant AGR2 fails to restore proteostasis or reduce BiP levels due to intrinsic functional impairment
Evidence from Studies
Supporting (1)
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Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel Disease
Contradicting (0)
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