Phosphorylated cingulin localises GEF-H1 at tight junctions to protect vascular barriers in blood endothelial cells

被引：11

作者：

Holzner, Silvio ^{[1
]}

Bromberger, Sophie ^{[1
]}

Wenzina, Judith ^{[1
]}

Neumuller, Karin ^{[1
]}

Holper, Tina-Maria ^{[2
]}

Petzelbauer, Peter ^{[1
]}

Bauer, Wolfgang ^{[2
]}

Weber, Benedikt ^{[1
]}

Schossleitner, Klaudia ^{[1
]}

机构：

[1] Med Univ Vienna, Dept Dermatol, Skin & Endothelium Res Div, A-1090 Vienna, Austria

[2] Med Univ Vienna, Dept Dermatol, A-1090 Vienna, Austria

来源：

JOURNAL OF CELL SCIENCE | 2021年 / 134卷 / 17期

关键词：

Cingulin; Tight junction; AMPK; Vascular barrier function; Guanine nucleotide exchange factors; Endothelium; KINASE; PERMEABILITY; EXPRESSION; RHO; DISRUPTION; THROMBIN; GENE;

D O I：

10.1242/jcs.258557

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Dysfunction of vascular barriers is a critical step in inflammatory diseases. Endothelial tight junctions (TJs) control barrier function, and the cytoplasmic adaptor protein cingulin connects TJs to signalling pathways. However, local events at TJs during inflammation are largely unknown. In this study, we investigate the local response of TJ adaptor protein cingulin and its interaction with Rho guanine nucleotide exchange factor H1 (GEF-H1, also known as ARHGEF2) upon vascular barrier disruption to find a new approach to counteract vascular leak. Based on transendothelial-electrical-resistance (TEER) measurements, cingulin strengthened barrier integrity upon stimulation with histamine, thrombin and VEGF. Cingulin also attenuated myosin light chain 2 (MLC2; also known as MYL2) phosphorylation by localising GEF-H1 to cell junctions. By using cingulin phosphomutants, we verified that the phosphorylation of the cingulin head domain is required for its protective effect. Increased colocalisation of GEF-H1 and cingulin was observed in the vessels of vasculitis patients compared to those in healthy skin. Our findings demonstrate that cingulin can counteract vascular leak at TJs, suggesting the existence of a novel mechanism in blood endothelial cells that protects barrier function during disease.

引用

页数：14

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