Ern2, also known as IRE1β, is an epithelial-specific endoplasmic reticulum (ER) stress sensor, a paralogue of ERN1/IRE1α. It plays a crucial role in mediating host-microbiota crosstalk. It is involved in the unfolded protein response pathway, especially in relation to mucus production and maintaining ER function [1,2,4].

Using Ern2-/-mice, researchers found that ERN2 is required for microbiota-induced goblet cell maturation and mucus barrier assembly in the colon. Normal gut microflora colonization induces Ern2 expression, and ERN2 acts by splicing Xbp1 mRNA to expand ER function and prevent ER stress in goblet cells. Mice lacking Ern2 have a dysbiotic microbial community, impaired goblet cell development, and increased susceptibility to colitis [1]. In Paneth cells, TNF signaling triggers the transcriptional downregulation of Ern2, leading to a reduction in antimicrobial peptide production, bacterial translocation, and subsequent polymicrobial sepsis [3].

In conclusion, Ern2 is essential for maintaining normal homeostasis at mucosal surfaces, especially in the colon, by regulating mucus layer assembly and shaping the gut microbiota composition. The use of Ern2-/-mouse models has revealed its significance in conditions like colitis and sepsis, providing insights into the mechanisms underlying host-microbe interactions and potential therapeutic targets for these diseases.

References:

1. Grey, Michael J, De Luca, Heidi, Ward, Doyle V, Turner, Jerrold R, Lencer, Wayne I. 2022. The epithelial-specific ER stress sensor ERN2/IRE1β enables host-microbiota crosstalk to affect colon goblet cell development. In The Journal of clinical investigation, 132, . doi:10.1172/JCI153519. https://pubmed.ncbi.nlm.nih.gov/35727638/

2. Tonelli, Claudia, Yordanov, Georgi N, Hao, Yuan, Preall, Jonathan, Tuveson, David A. 2024. A mucus production programme promotes classical pancreatic ductal adenocarcinoma. In Gut, 73, 941-954. doi:10.1136/gutjnl-2023-329839. https://pubmed.ncbi.nlm.nih.gov/38262672/

3. Wallaeys, Charlotte, Garcia-Gonzalez, Natalia, Timmermans, Steven, Iwawaki, Takao, Libert, Claude. 2024. Paneth cell TNF signaling induces gut bacterial translocation and sepsis. In Cell host & microbe, 32, 1725-1743.e7. doi:10.1016/j.chom.2024.08.007. https://pubmed.ncbi.nlm.nih.gov/39243761/

4. Johansson, Malin Ev, Hansson, Gunnar C. . Goblet cells need some stress. In The Journal of clinical investigation, 132, . doi:10.1172/JCI162030. https://pubmed.ncbi.nlm.nih.gov/36047499/