Insights into the role of LEPRE-1 in Unfolded Protein Response and in Paneth / goblet cell specification

Unfolded Protein Response (UPR) functions as a fundamental signaling process to cope with internal and external stress. In a search for candidates whose mRNA translation relies on the U34 tRNA-modifying enzyme ELP3 in intestinal epithelial cells (IECs), we identified the collagen prolyl 3-hydroxylase LEPRE-1, whose loss-of-function mutation causes Osteogenesis Imperfecta (OI) in human. Epithelial LEPRE-1 is an ER-located protein that the deficiency of LEPRE-1 can lead to disturbed activation of UPR signaling. As UPR signaling interacts with many other signaling pathways, including Wnt and Notch signaling, LEPRE-1 can thus impact the expression of some Wnt and Notch effectors, which are involved in IEC differentiation. Likewise, the conditional knockout of Lepre-1 in mouse intestinal epithelium impairs Paneth cell differentiation and the production of defensin α5. As a result, mice with Lepre-1 deficiency in IECs are more sensitive to experimental colitis as they show a more severe inflammatory phenotype. Lepre-1 deficiency also potentiates goblet cell differentiation, suggesting that the Paneth/goblet cell fate specification can be affected by Lepre-1. Collectively, our data define epithelial LEPRE-1 as a player in UPR signaling, a candidate that prevents excessive intestinal inflammation, and a regulator of intestinal cell fate specification.