Type I Interferons Control Proliferation and Function of Intestinal Epithelium

Wnt pathway-driven proliferation and renewal of the intestinal epithelium must be tightly controlled to prevent development of cancer and barrier dysfunction. Although type 1 interferons (IFN) produced in the gut under influence of microbiota are known for their anti-proliferative effects, the role of these cytokines in regulating intestinal epithelial renewal is largely unknown. Here we report a novel role for IFN in the context of intestinal knockout of casein kinase 1α (CK1α), which controls ubiquitination and degradation of both β-catenin and the IFNAR1 chain of the IFN receptor. Ablation of CK1α leads to activation of both β-catenin and IFN pathway and prevents unlimited proliferation of intestinal epithelial cells despite constitutive β-catenin activity. IFN signaling contributes to activation of the p53 pathway and appearance of apoptotic and senescence markers in the CK1α-deficient gut. Concurrent genetic ablation of CK1α and IFNAR1 leads to intestinal hyperplasia, robust attenuation of apoptosis, and rapid and lethal loss of the barrier function. These data indicate that IFN plays an important role in controlling proliferation and function of intestinal epithelium in the context of β-catenin activation. Two conditions were examined, with 2 replicates for each condition, yielding 4 samples in total.