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Inflammatory Bowel Diseases:
doi: 10.1097/MIB.0000000000000010
Original Basic Science Articles

Phosphorylation of eIF2α Is Dispensable for Differentiation but Required at a Posttranscriptional Level for Paneth Cell Function and Intestinal Homeostasis in Mice

Cao, Stewart S. PhD*,†; Wang, Miao MD, PhD*; Harrington, Jane C. PhD; Chuang, Brandy-Mengchieh BS*; Eckmann, Lars MD; Kaufman, Randal J. PhD*

Supplemental Author Material
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Abstract

Background:

Recent studies link endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) to inflammatory bowel disease. Altered eIF2α phosphorylation (eIF2α-P), a regulatory hub of the UPR, was observed in mucosal tissue of patients with inflammatory bowel disease. In this study, we examined the mechanistic role of eIF2α-P in intestinal epithelial cell (IEC) function and intestinal homeostasis in mice.

Methods:

We generated mice with villin-Cre-mediated conditional expression of nonphosphorylatable Ser51Ala mutant eIF2α in IECs (AAIEC mice). We analyzed AAIEC mice under normal conditions and on challenge with oral infection of Salmonella Typhimurium or dextran sulfate sodium-induced colitis.

Results:

Loss of eIF2α-P did not affect the normal proliferation or differentiation of IECs. However, AAIEC mice expressed decreased secretory proteins including lysozyme, suggesting eIF2α-P is required for Paneth cell function. The ultrastructure of AA Paneth cells exhibited a reduced number of secretory granules, a fragmented ER, and distended mitochondria under normal conditions. UPR gene expression was defective in AA IECs. Translation of Paneth cell specific messenger RNAs encoding lysozyme and cryptidins was significantly defective leading to the observed granule-deficient phenotype, which was associated with reduced ribosomal recruitment of these messenger RNAs to the ER membrane. Consequently, AAIEC mice were more susceptible to oral Salmonella infection and dextran sulfate sodium-induced colitis.

Conclusions:

We conclude eIF2α phosphorylation is required for the normal function of intestinal Paneth cells and mucosal homeostasis by activating UPR signaling and promoting messenger RNA recruitment to the ER membrane for translation.

Copyright © 2014 Crohn's & Colitis Foundation of America, Inc.

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