Translation Initiation Factor eIF2Bε Promotes Stemness of Intestinal Epithelial Cells

Modulation of global mRNA translation is essential for intestinal stem cell function. In colorectal cancer, proliferating stem-like cells are defined by high WNT signaling and display dysregulated translational control. It is currently unclear how factors that coordinate global translation affect stem cell behavior. Here we identified nucleotide exchange factor eIF2Be as a translation initiation factor involved in intestinal epithelial stemness. In eIF2Be Arg191His mice, which have a homozygous point mutation that intrinsically impairs eIF2Be’s enzymatic function, we demonstrate that dysfunctional eIF2Be affects small intestinal crypt formation, proliferation and stemness marker expression. By hyperactivating stem cell activity in ex vivo organoids, using a GSK3β inhibitor to mimic loss of tumor suppressor Apc , we demonstrate that eIF2Be is essential for clonogenic potential and associated with an increase in global translation. Finally, we observe high eIF2Be expression in human colonic adenoma tissues, exposing eIF2Be as a potential target in modulation of stemness.