α4 Coordinates Small Intestinal Epithelium Homeostasis by Regulating Stability of HuR

The mammalian intestinal epithelium is a rapidly self-renewing tissue in the body, and its homeostasis depends on a dynamic balance among proliferation, migration, apoptosis, and differentiation of intestinal epithelial cells (IECs). The protein phosphatase 2A (PP2A)-associated protein α4 controls the activity and specificity of serine/threonine phosphatases and is thus implicated in many cellular processes. Here, using a genetic approach, we investigated the mechanisms whereby α4 controls the homeostasis of the intestinal epithelium. In mice with ablated α4, the small intestinal mucosa exhibited crypt hyperplasia, villus shrinkage, defective differentiation of Paneth cells, and reduced IEC migration along the crypt-villus axis. The α4-deficient intestinal epithelium also displayed decreased expression of different intercellular junction proteins and abnormal epithelial permeability. In addition, α4 deficiency decreased the levels of the RNA-binding protein HuR in the mucosal tissue. In cultured IECs, ectopic overexpression of HuR in α4-deficient cells rescued the production of these intercellular junction proteins and restored the epithelial barrier function to a nearly normal level. Mechanistically, α4 silencing destabilized HuR through a process involving HuR phosphorylation by IκB kinase α, leading to ubiquitin-mediated proteolysis of HuR. These findings indicate that the critical impact of α4 upon the barrier function and homeostasis of the intestinal epithelium depends largely on its ability to regulate the stability of HuR.