The protein disulfide isomerase AGR2 is essential for production of intestinal mucus
- 28 April 2009
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 106 (17), 6950-6955
- https://doi.org/10.1073/pnas.0808722106
Abstract
Protein disulfide isomerases (PDIs) aid protein folding and assembly by catalyzing formation and shuffling of cysteine disulfide bonds in the endoplasmic reticulum (ER). Many members of the PDI family are expressed in mammals, but the roles of specific PDIs in vivo are poorly understood. A recent homology-based search for additional PDI family members identified anterior gradient homolog 2 (AGR2), a protein originally presumed to be secreted by intestinal epithelial cells. Here, we show that AGR2 is present within the ER of intestinal secretory epithelial cells and is essential for in vivo production of the intestinal mucin MUC2, a large, cysteine-rich glycoprotein that forms the protective mucus gel lining the intestine. A cysteine residue within the AGR2 thioredoxin-like domain forms mixed disulfide bonds with MUC2, indicating a direct role for AGR2 in mucin processing. Mice lacking AGR2 were viable but were highly susceptible to colitis, indicating a critical role for AGR2 in protection from disease. We conclude that AGR2 is a unique member of the PDI family, with a specialized and nonredundant role in intestinal mucus production.Keywords
This publication has 41 references indexed in Scilit:
- Colonic gene expression profile in NHE3-deficient mice: evidence for spontaneous distal colitisAmerican Journal of Physiology-Gastrointestinal and Liver Physiology, 2008
- Aberrant Mucin Assembly in Mice Causes Endoplasmic Reticulum Stress and Spontaneous Inflammation Resembling Ulcerative ColitisPLoS Medicine, 2008
- A critical role for extracellular protein disulfide isomerase during thrombus formation in miceJCI Insight, 2008
- Protein disulfide isomerase acts as an injury response signal that enhances fibrin generation via tissue factor activationJCI Insight, 2008
- A molecular specificity code for the three mammalian KDEL receptorsThe Journal of cell biology, 2007
- Dietary phytochemicals regulate whole-body CYP1A1 expression through an arylhydrocarbon receptor nuclear translocator–dependent system in gutJCI Insight, 2007
- ERp57 is essential for efficient folding of glycoproteins sharing common structural domainsThe EMBO Journal, 2006
- Significance of the metastasis-inducing protein AGR2 for outcome in hormonally treated breast cancer patientsBritish Journal of Cancer, 2006
- Diversity of the protein disulfide isomerase family: Identification of breast tumor induced Hag2 and Hag3 as novel members of the protein familyMolecular Phylogenetics and Evolution, 2005
- Analysis of gene expression in cancer cell lines identifies candidate markers for pancreatic tumorigenesis and metastasisInternational Journal of Cancer, 2004