Impact of unfolded protein responses on intestinal epithelial homeostasis in genetically modified mouse models

The intestinal epithelium is the key interface between luminal factors of the gut and the mucosal immune system of the host receiving and processing manifold signals from both sides. One set of signal processing programs are the unfolded protein responses (UPR) of the endoplasmic reticulum (ER) and the mitochondria (MT). If those UPR appear de-regulated in intestinal epithelial cells (IEC), they compromise epithelial function and favor the onset of inflammatory bowel diseases (IBD). This study investigates the impact of persistently activated ER- and MT-UPR pathways in IEC on epithelial homeostasis by the use of genetically modified mouse models. Besides models overexpressing ER-UPR derived transcription factors, we generated IEC-specific knockout mice lacking the MT-UPR associated chaperone heat shock protein 60 (HSP60). We could show that deletion of Hsp60 disrupts epithelial cell homeostasis in both the pre- and postnatal gut, independent of an inflammation-associated pathology. HSP60 deficiency in the intestinal epithelium triggers MT-UPR, leading to an impaired proliferative response and a loss of stem cells. This study substantiates the impact of organelle specific UPR mechanisms on epithelial homeostasis, especially on epithelial cell proliferation and stemness.