Loss of VMP1 Impairs Tight Junction Recycling and Aggravates Intestinal Barrier Dysfunction in Inflammatory Bowel...

Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the gastrointestinal tract. This disease is characterized by a steadily increasing global incidence. Multiple susceptibility genes are implicated in IBD pathogenesis. However, the molecular mechanisms linking epithelial barrier dysfunction to disease progression remain poorly understood. This study performs an integrative analysis of public bulk RNA-seq and single-cell transcriptomic datasets. Experimental validation is conducted using clinical samples. Analyses reveal that vacuole membrane protein 1 (VMP1) is significantly downregulated in IBD. This reduced expression correlates with disease severity. Functional studies demonstrate that VMP1 deficiency in intestinal epithelial cells disrupts tight junction integrity. This loss increases epithelial permeability and exacerbates intestinal inflammation. Mechanistically, VMP1 facilitates the recruitment of CORO1C to late endosomes. This recruitment promotes Retromer-mediated recycling of the tight junction protein Occludin to the plasma membrane. Impairment of this pathway shifts Occludin trafficking toward ESCRT-dependent microautophagic degradation. This shift results in the sustained loss of tight junctions. These findings identify VMP1 as a previously unrecognized regulator of epithelial tight junction recycling and barrier homeostasis. This discovery provides new mechanistic insights into IBD pathogenesis and highlights a promising therapeutic avenue for restoring intestinal barrier function.