Neuropilin 1 and its inhibitory ligand mini-tryptophanyl-tRNA synthetase inversely regulate VE-cadherin turnover and vascular permeability.
Neuropilin 1 and its inhibitory ligand mini-tryptophanyl-tRNA synthetase inversely regulate VE-cadherin turnover and vascular permeability.
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DOI：
10.1038/s41467-022-31904-1
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发表时间：
2022-07-20
影响因子：
16.6
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中科院分区：
文献类型：
--
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功能性血管网络的形成依赖于内皮细胞（ECs）根据血流以及血管内皮生长因子 - A（VEGF - A）和第3类信号素（SEMA3s）等导向信号动态重排其黏附连接的能力。神经毡蛋白1（NRP1）对血管发育至关重要，且其作用不依赖于配体VEGF - A和SEMA3，但其机制尚不清楚。基于无偏蛋白质组学分析，我们在此报道，NRP1主要作为未受刺激的内皮细胞表面黏附受体的内吞伴侣发挥作用。NRP1定位于黏附连接（AJs）处，在那里它与血管内皮钙黏蛋白（VE - cadherin）相互作用，促进其基础的内吞依赖型转换，并有利于在培养的内皮细胞和小鼠中由组胺引发的血管通透性。我们鉴定出色氨酸 - tRNA合成酶的一种剪接变体（小色氨酰 - tRNA合成酶，mini - WARS）作为NRP1的一种非常规分泌的细胞外抑制性配体，它通过使NRP1在黏附连接（AJs）处稳定，减缓血管内皮钙黏蛋白的转换以及组胺引发的内皮渗漏。因此，我们的工作表明NRP1作为黏附连接可塑性的主要调节因子的作用，并揭示了小色氨酰 - tRNA合成酶（mini - WARS）如何作为一种生理性的NRP1抑制性配体来控制血管内皮钙黏蛋白的内吞转换和血管通透性。
功能性血管树的形成在许多情况下（如癌症）是关键步骤，并且神经毡蛋白1（NRP1）与黏附受体的内吞转换有关。在此，作者表明NRP1及其小色氨酰 - tRNA合成酶（mini - WARS）配体在降低内皮通透性方面发挥作用。
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. Functional vascular tree formation is a key step in many contexts, such as cancer, and Neuropilin1 (NRP1) has been associated with adhesion receptor endocytic turnover. Here, authors show NRP1 and its mini-WARS ligand play a role in reducing endothelial permeability.
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影响因子：
6.7
作者：
Goddard LM;Iruela-Arispe ML
通讯作者：
Iruela-Arispe ML
影响因子：
9.8
作者：
Astrof S;Hynes RO
通讯作者：
Hynes RO
影响因子：
16.6
作者：
Cruys B;Wong BW;Kuchnio A;Verdegem D;Cantelmo AR;Conradi LC;Vandekeere S;Bouché A;Cornelissen I;Vinckier S;Merks RM;Dejana E;Gerhardt H;Dewerchin M;Bentley K;Carmeliet P
通讯作者：
Carmeliet P
影响因子：
4
作者：
De Franceschi N;Hamidi H;Alanko J;Sahgal P;Ivaska J
通讯作者：
Ivaska J
影响因子：
4.4
作者：
Cox, Juergen;Neuhauser, Nadin;Mann, Matthias
通讯作者：
Mann, Matthias