The protein disulfide isomerase AGR2 is essential for production of intestinal mucus

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 thioredoxinlike 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.colitis ͉ endoplasmic reticulum ͉ mucin ͉ goblet cell ͉ protein processing

Small Airways in Asthma: Distal is Different

“…Beside its role in the intestine, Agr2 is also expressed in mucus-producing goblet cells and localizes with Muc5AC during airway GCM in a mouse model of experimental allergic asthma. Thus, Agr2 deficient mice display impaired export of mucins from the ER and no activation of UPR [61][62][63]. These studies support the role of Agr2 in reducing ER stress during the production of large amounts of mucins.…”

“…These studies support the role of Agr2 in reducing ER stress during the production of large amounts of mucins. Consistent with its role in mucus processing the expression of Agr2 in airway epithelial cells is regulated via the IL-13-dependent STAT-6 pathway and Spdef [61,63]. Recently, Foxp1 was identified as another transcriptional regulator of Agr2.…”

“…PDI proteins support the transition of proteins to the ER by the rearrangement of disulfide bonds in incorrectly folded substrate proteins [59]. Agr2 was initially described to play a role in the production of the intestinal mucus protein Muc2 [60], but also as a chaperone required for mucin packaging [61]. Beside its role in the intestine, Agr2 is also expressed in mucus-producing goblet cells and localizes with Muc5AC during airway GCM in a mouse model of experimental allergic asthma.…”

Hydrogen peroxide mediated mitochondrial UNG1-PRDX3 interaction and UNG1 degradation

“…AGR2 was discovered in Xenopus laevis and is associated with cement gland differentiation [32]. As a member of the protein disulfide isomerase family, AGR2 has a thioredoxin-like domain to aid protein folding and assembly [33,34] and its expression is elevated in the preneoplastic tissue in Barrett's oesophagus and other human cancer cells, where it functions as a proto-oncogene [35][36][37]. AGR2 interacts with multiple proteins including DNA binding proteins and AAA þ ATPase [37][38][39].…”

The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host–microbial interactions

“…Mice with a mutation in the endoplasmic reticulum stress response key regulator XBP1 are more susceptible to induced colitis (28), but how this affects Muc2 has not been studied. The Agr2 protein, which has a special thioredoxin-like domain, is essential for the in vivo production of Muc2, and Agr2-null mice are highly susceptible to colitis (29,30). Finally, it has also been observed that several mouse strains with mutations causing a dysfunctional Muc2 mucin show a strong unfolded response (31).…”