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.
CRCINA, CNRS, INSERM, Université de Nantes, France.|Team SOAP, 'Signaling in Oncogenesis, Angiogenesis, and Permeability', Nantes, France.|CNRS, INSERM, Institut Cochin, Université Paris Descartes, France.
Héloïse M
HM
Leclair
CRCINA, CNRS, INSERM, Université de Nantes, France.|Team SOAP, 'Signaling in Oncogenesis, Angiogenesis, and Permeability', Nantes, France.
Gwennan
G
André-Grégoire
CNRS, INSERM, Institut Cochin, Université Paris Descartes, France.
Lucas
L
Treps
CNRS, INSERM, Institut Cochin, Université Paris Descartes, France.
Sandy
S
Azzi
CRCINA, CNRS, INSERM, Université de Nantes, France.|Team SOAP, 'Signaling in Oncogenesis, Angiogenesis, and Permeability', Nantes, France.|CNRS, INSERM, Institut Cochin, Université Paris Descartes, France.
Nicolas
N
Bidère
CRCINA, CNRS, INSERM, Université de Nantes, France. julie.gavard@inserm.fr.|Team SOAP, 'Signaling in Oncogenesis, Angiogenesis, and Permeability', Nantes, France. julie.gavard@inserm.fr.|CNRS, INSERM, Institut Cochin, Université Paris Descartes, France. julie.gavard@inserm.fr.
Julie
J
Gavard
D001812:Blood-Brain Barrier / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004727:Endothelium / Q000378:metabolism*; D000071161:Forkhead Box Protein O1 / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D062793:Occludin / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; C502926:MARCHF2 protein, human; D044767:Ubiquitin-Protein Ligases
FoxO; claudin-5; occludin; permeability; tight junction; ubiquitin