The endoplasmic reticulum (ER) is responsible for the synthesis, folding and structural maturation of proteins. When protein-folding requirements exceed the processing capacity of the ER, misfolded and unfolded proteins accumulate in the ER lumen, leading to a condition termed ER stress.

ER stress results in the activation of a complex adaptive signaling pathway called the Unfolded Protein Response (UPR), which, in case of irremediable ER stress, can drive cells into apoptosis. Activation of all three branches of the UPR – namely IRE1/XBP1, ATF6 and PERK/ATF4/CHOP – is observed in a broad number of chronic disorders including inflammatory bowel disease (IBD). Whereas Kaser et al. (2008) as well as Niederreiter et al. (2013) describe that loss of the IRE1/XBP1 branch of the UPR in highly secretory epithelial cells result in spontaneous intestinal inflammation in mice, CHOP-deficient mice are even protected from DSS-induced colitis. Thus, a complex inter-crosstalk of the UPR pathways is assumed to contribute to disease development and progression. Here, we hypothesize that also other IBD risk genes might interfere with ER stress signaling, thereby regulating disease severity and/or progression.