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Ubiquitin ligase CHFR mediated degradation of VE-cadherin through ubiquitylation disrupts endothelial adherens junctions

Author

Listed:
  • Chinnaswamy Tiruppathi

    (University of Illinois College of Medicine)

  • Dong-Mei Wang

    (University of Illinois College of Medicine)

  • Mohammad Owais Ansari

    (University of Illinois College of Medicine)

  • Shabana Bano

    (University of Illinois College of Medicine)

  • Yoshikazu Tsukasaki

    (University of Illinois College of Medicine)

  • Amitabha Mukhopadhyay

    (University of Illinois College of Medicine)

  • Jagdish C. Joshi

    (University of Illinois College of Medicine)

  • Christian Loch

    (AVMBioMed)

  • Hans W. M. Niessen

    (VU University Medical Center)

  • Asrar B. Malik

    (University of Illinois College of Medicine)

Abstract

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 (ChfrΔEC) mice. We also observe abrogation of LPS-induced degradation of VE-cadherin in ChfrΔEC 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 ChfrΔEC 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.

Suggested Citation

  • Chinnaswamy Tiruppathi & Dong-Mei Wang & Mohammad Owais Ansari & Shabana Bano & Yoshikazu Tsukasaki & Amitabha Mukhopadhyay & Jagdish C. Joshi & Christian Loch & Hans W. M. Niessen & Asrar B. Malik, 2023. "Ubiquitin ligase CHFR mediated degradation of VE-cadherin through ubiquitylation disrupts endothelial adherens junctions," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42225-2
    DOI: 10.1038/s41467-023-42225-2
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    References listed on IDEAS

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    1. Fabrizio Orsenigo & Costanza Giampietro & Aldo Ferrari & Monica Corada & Ariane Galaup & Sara Sigismund & Giuseppe Ristagno & Luigi Maddaluno & Gou Young Koh & Davide Franco & Vartan Kurtcuoglu & Dimo, 2012. "Phosphorylation of VE-cadherin is modulated by haemodynamic forces and contributes to the regulation of vascular permeability in vivo," Nature Communications, Nature, vol. 3(1), pages 1-15, January.
    2. Menglin Liu & Lianghui Zhang & Glenn Marsboom & Ankit Jambusaria & Shiqin Xiong & Peter T. Toth & Elizaveta V. Benevolenskaya & Jalees Rehman & Asrar B. Malik, 2019. "Sox17 is required for endothelial regeneration following inflammation-induced vascular injury," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
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