Neuropilin 1 and its inhibitory ligand mini-tryptophanyl-tRNA synthetase inversely regulate VE-cadherin turnover and vascular permeability

Gioelli, N. et al. (2022) Neuropilin 1 and its inhibitory ligand mini-tryptophanyl-tRNA synthetase inversely regulate VE-cadherin turnover and vascular permeability. Nature Communications, 13, 4188. (doi: 10.1038/s41467-022-31904-1) (PMID:35858913) (PMCID:PMC9300702)

Abstract

The formation of a functional blood vessel network relies on the ability of endothelial cells (ECs) to dynamically rearrange their adhesive contacts in response to blood flow and guidance cues, such as vascular endothelial growth factor-A (VEGF-A) and class 3 semaphorins (SEMA3s). Neuropilin 1 (NRP1) is essential for blood vessel development, independently of its ligands VEGF-A and SEMA3, through poorly understood mechanisms. Grounding on unbiased proteomic analysis, we report here that NRP1 acts as an endocytic chaperone primarily for adhesion receptors on the surface of unstimulated ECs. NRP1 localizes at adherens junctions (AJs) where, interacting with VE-cadherin, promotes its basal internalization-dependent turnover and favors vascular permeability initiated by histamine in both cultured ECs and mice. We identify a splice variant of tryptophanyl-tRNA synthetase (mini-WARS) as an unconventionally secreted extracellular inhibitory ligand of NRP1 that, by stabilizing it at the AJs, slows down both VE-cadherin turnover and histamine-elicited endothelial leakage. Thus, our work shows a role for NRP1 as a major regulator of AJs plasticity and reveals how mini-WARS acts as a physiological NRP1 inhibitory ligand in the control of VE-cadherin endocytic turnover and vascular permeability.

• Item Type: Articles
• Additional Information: The research leading to these results has received funding from: AIRC under IG 2018— ID. 21315—P.I. Serini Guido, IG 2017—ID. 20366—P.I. Valdembri Donatella, IG 2017— ID. 19957—P.I. Enrico Giraudo; AIRC under 5 per Mille 2018—ID. 21052 program—P.I. Comoglio Paolo, G.L.s Serini Guido and Enrico Giraudo (to G.S. and E.G.); FPRCONLUS Grant “MIUR 2010 Vaschetto—5 per mille 2010 MIUR” (to G.S.); Telethon Italy (GGP09175) (to G.S.); Associazione ‘Augusto per la Vita’ (to G.S.); Ministero dell’Istruzione, dell’Università e della Ricerca (PRIN 2020EK82R5) (to G.S.); Università di Torino, Bando Ricerca Locale 2019 (CUP D84I19002940005) (to G.S.); PTCRC-Intra 2020 FPRC 5xmille 2017 Ministero Salute, project “SEE-HER” (to E.G.); CRUK Beatson Institute A31287, CRUK Glasgow Centre A18076 and Stand Up to Cancer campaign for Cancer Research UK A29800 (to S.Z.); long-term structural Methusalem funding from the Flemish government (to M.M.).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Zanivan, Professor Sara
• Authors: Gioelli, N., Neilson, L. J., Wei, N., Villari, G., Chen, W., Kuhle, B., Ehling, M., Maione, F., Willox, S., Brundu, S., Avanzato, D., Koulouras, G., Mazzone, M., Giraudo, E., Yang, X.-L., Valdembri, D., Zanivan, S., and Serini, G.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © The Author(s) 2022
• First Published: First published in Nature Communications 13: 4188
• Publisher Policy: Reproduced under a Creative Commons licence