The E3 ubiquitin ligase MARCH3 controls the endothelial barrier

Cell-cell contacts coordinate the endothelial barrier function in response to external cues. To identify new mediators involved in cytokine-promoted endothelial permeability, we screened a siRNA library targeting E3 ubiquitin ligases. Here, we report that silencing of the late endosome/lysosomal membrane-associated RING-CH-3 (MARCH3) enzyme protects the endothelial barrier. Furthermore, transcriptome analysis unmasked the upregulation of the tight junction-encoding gene occludin (OCLN) in MARCH3-depleted cells. Indeed, MARCH3 silencing results in the strengthening of cell-cell contacts, as evidenced by the accumulation of junctional proteins. From a molecular standpoint, the FoxO1 forkhead transcription repressor was inactivated in the absence of MARCH3. This provides a possible molecular link between MARCH3 and the signaling pathway involved in regulating the expression of junctional proteins and barrier integrity.