Junctional plakoglobin regulates intestinal epithelial cell proliferation via MAPK/ERK signaling

Junctional plakoglobin (JUP) is a desmosomal protein essential for epithelial tissue integrity and epithelial-immune cell crosstalk. Although JUP has been implicated in inflammatory processes, its role in intestinal epithelial repair remains unclear. In vitro, loss of JUP in Caco-2 monolayers and non-transformed intestinal organoids markedly accelerated wound closure, driven by enhanced epithelial cell migration and proliferation. RNA sequencing-based pathway analysis of organoids revealed activation of MAPK/ERK signaling following JUP deficiency. This effect was corroborated by increased ERK phosphorylation in Western blot analyses. In line with that, pharmacological inhibition of ERK abrogated the accelerated wound closure, confirming that MAPK/ERK signaling is critical for the phenotype. To further examine the relevance in vivo, we used an inducible, intestine-specific JUP knockout mouse model (iVilCreER T2 Jup fl/fl ). Following biopsy-induced intestinal injury, JUP deletion significantly enhanced mucosal repair, accompanied by increased cell proliferation and MAPK signaling, thereby confirming the in vitro results. Collectively, these findings establish JUP as a previously unrecognized regulator of epithelial cell dynamics and repair through MAPK/ERK signaling. Loss of epithelial plakoglobin (JUP) activates MAPK/ERK signaling, thus, significantly enhancing epithelial cell motility by increased cell proliferation and migration. The signaling cascade accelerates wound closure in vitro and in vivo, thereby improving intestinal mucosal healing following injury.