Localized regulation of cell junction mRNAs is required for epithelial cell integrity.

Abstract

Epithelial cells exhibit a highly polarized organization along their apico-basal axis, a feature that is critical to their function and is frequently perturbed in cancer. One less explored process modulating epithelial cell polarity is the subcellular localization of mRNA molecules. In this study, we report that several mRNAs encoding evolutionarily conserved epithelial polarity regulatory proteins, including <i>Zo-1</i>, <i>Afdn</i>, and <i>Scrib</i>, are localized to cell junction regions in <i>Drosophila</i> epithelial tissues and human epithelial cells. Targeting of these mRNAs coincides with robust junctional distribution of their encoded proteins, and these transcripts are translated in proximity to cell junction regions. Through systematic immunolabeling, we identify a collection of RNA binding proteins with cell junction distribution patterns, several of which associate with junctional transcripts and are functionally required for proper targeting of ZO-1 and SCRIB proteins. Loss of function of two candidate factors, MAGOH and PCBP3, differentially impacts junctional mRNA, with MAGOH knockdown reducing <i>Zo-1</i> and <i>Scrib</i> transcript targeting and localized translation, while PCBP3 knockdown only perturbs local translation. Depletion of <i>Drosophila</i> MAGO in vivo in follicular epithelial cells also disrupts the distribution of junctional transcripts and proteins. Finally, through tissue microarray analysis of ovarian cancer tumor specimens, we find that the expression of MAGOH and ZO-1 is positively correlated and that both proteins are potential biomarkers of good prognosis. We conclude that localized mRNA regulation at cell junction regions is important for modulating epithelial cell integrity.