TY - JOUR
T1 - Ubiquitin ligase CHFR mediated degradation of VE-cadherin through ubiquitylation disrupts endothelial adherens junctions
AU - Tiruppathi, Chinnaswamy
AU - Wang, Dong-Mei
AU - Ansari, Mohammad Owais
AU - Bano, Shabana
AU - Tsukasaki, Yoshikazu
AU - Mukhopadhyay, Amitabha
AU - Joshi, Jagdish C.
AU - Loch, Christian
AU - Niessen, Hans W. M.
AU - Malik, Asrar B.
N1 - Funding Information: This work was funded by NIH grants: R01GM138499 (C.T.), R01HL156965 (C.T.), and P01HL160469-project 2 (A.B.M). The schematic diagrams were made using Biorender.com. Publisher Copyright: © 2023, Springer Nature Limited.
PY - 2023/12/1
Y1 - 2023/12/1
N2 - Vascular endothelial cadherin (VE-cadherin) expressed at endothelial adherens junctions (AJs) is vital for vascular integrity and endothelial homeostasis. Here we identify the requirement of the ubiquitin E3-ligase CHFR as a key mechanism of ubiquitylation-dependent degradation of VE-cadherin. CHFR was essential for disrupting the endothelium through control of the VE-cadherin protein expression at AJs. We observe augmented expression of VE-cadherin in endothelial cell (EC)-restricted Chfr knockout (Chfr ΔEC) mice. We also observe abrogation of LPS-induced degradation of VE-cadherin in Chfr ΔEC mice, suggesting the pathophysiological relevance of CHFR in regulating the endothelial junctional barrier in inflammation. Lung endothelial barrier breakdown, inflammatory neutrophil extravasation, and mortality induced by LPS were all suppressed in Chfr ΔEC mice. We find that the transcription factor FoxO1 is a key upstream regulator of CHFR expression. These findings demonstrate the requisite role of the endothelial cell-expressed E3-ligase CHFR in regulating the expression of VE-cadherin, and thereby endothelial junctional barrier integrity.
AB - Vascular endothelial cadherin (VE-cadherin) expressed at endothelial adherens junctions (AJs) is vital for vascular integrity and endothelial homeostasis. Here we identify the requirement of the ubiquitin E3-ligase CHFR as a key mechanism of ubiquitylation-dependent degradation of VE-cadherin. CHFR was essential for disrupting the endothelium through control of the VE-cadherin protein expression at AJs. We observe augmented expression of VE-cadherin in endothelial cell (EC)-restricted Chfr knockout (Chfr ΔEC) mice. We also observe abrogation of LPS-induced degradation of VE-cadherin in Chfr ΔEC mice, suggesting the pathophysiological relevance of CHFR in regulating the endothelial junctional barrier in inflammation. Lung endothelial barrier breakdown, inflammatory neutrophil extravasation, and mortality induced by LPS were all suppressed in Chfr ΔEC mice. We find that the transcription factor FoxO1 is a key upstream regulator of CHFR expression. These findings demonstrate the requisite role of the endothelial cell-expressed E3-ligase CHFR in regulating the expression of VE-cadherin, and thereby endothelial junctional barrier integrity.
UR - http://www.scopus.com/inward/record.url?scp=85174457013&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-023-42225-2
DO - https://doi.org/10.1038/s41467-023-42225-2
M3 - Article
C2 - 37852964
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 6582
ER -