MARCH family E3 ubiquitin ligases selectively target and degrade cadherin family proteins.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Cadherins*/metabolism ; Proteolysis* ; Ubiquitin-Protein Ligases*/metabolism ; Ubiquitin-Protein Ligases*/genetics; Humans ; Adherens Junctions/metabolism ; Antigens, CD/metabolism ; Antigens, CD/genetics ; Cell Adhesion ; HEK293 Cells ; Membrane Proteins/genetics ; Membrane Proteins/metabolism

Cadherin family proteins play a central role in epithelial and endothelial cell-cell adhesion. The dynamic regulation of cell adhesion is achieved in part through endocytic membrane trafficking pathways that modulate cadherin cell surface levels. Here, we define the role for various MARCH family ubiquitin ligases in the regulation of cadherin degradation. We find that MARCH2 selectively downregulates VE-cadherin, resulting in loss of adherens junction proteins at cell borders and a loss of endothelial barrier function. Interestingly, N-cadherin is refractory to MARCH ligase expression, demonstrating that different classical cadherin family proteins are differentially regulated by MARCH family ligases. Using chimeric cadherins, we find that the specificity of different MARCH family ligases for different cadherins is conferred by the cadherin transmembrane domain. Further, juxta-membrane lysine residues are required for cadherin degradation by MARCH proteins. These findings expand our understanding of cadherin regulation and highlight a new role for mammalian MARCH family ubiquitin ligases in differentially regulating cadherin turnover.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Seo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Update of: bioRxiv. 2023 Aug 10:2023.08.10.552739. doi: 10.1101/2023.08.10.552739. (PMID: 37609155)

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R01 AR048266 United States AR NIAMS NIH HHS; R01 AR050501 United States AR NIAMS NIH HHS; R56 AR048266 United States AR NIAMS NIH HHS

0 (Antigens, CD)
0 (cadherin 5)
0 (Cadherins)
EC 2.3.2.27 (MARCHF2 protein, human)
0 (Membrane Proteins)
EC 2.3.2.27 (Ubiquitin-Protein Ligases)

Date Created: 20240509 Date Completed: 20240509 Latest Revision: 20240612

20240613

PMC11081302

10.1371/journal.pone.0290485

38722959