TFEB controls integrin-mediated endothelial cell adhesion by the regulation of cholesterol metabolism

Abstract

The dynamic integrin-mediated adhesion of endothelial cells (ECs) to the surrounding ECM is fundamental for angiogenesis both in physiological and pathological conditions, such as embryonic development and cancer progression. The dynamics of EC-to-ECM adhesions relies on the regulation of the conformational activation and trafficking of integrins. Here, we reveal that oncogenic transcription factor EB (TFEB), a known regulator of lysosomal biogenesis and metabolism, also controls a transcriptional program that influences the turnover of ECM adhesions in ECs by regulating cholesterol metabolism. We show that TFEB favors ECM adhesion turnover by promoting the transcription of genes that drive the synthesis of cholesterol, which promotes the aggregation of caveolin-1, and the caveolin-dependent endocytosis of integrin β1. These findings suggest that TFEB might represent a novel target for the pharmacological control of pathological angiogenesis and bring new insights in the mechanism sustaining TFEB control of endocytosis.

Free fatty acids stabilize integrin β1 via S-nitrosylation to promote monocyte–endothelial adhesion

“…In parallel, S-nitrosylation of endothelial VCAM needs to be further investigated. Moreover, after binding to VCAM on the surface of endothelial cells, integrin β 1 undergoes caveolar endocytosis and then routes for degradation ( 43 ). However, the regulation of S-nitrosylation on integrin β 1 endocytosis warrants further investigation.…”

Intracellular Membrane Transport in Vascular Endothelial Cells

“…In the aorta, due to the fact that the wall and BM are constantly distended and then relaxed, BM is mesh-like rather than solid [ 6 ]. The BM proteins are secreted through BLPM, whereas proteins providing anti-thrombogenicity of ECs are secreted through APM [ 16 , 83 , 84 , 85 ]. In particular, integrins are delivered to the BLPM, and highly glycosylated proteins forming the glycocalyx are delivered to the APM.…”

Transcription factor EB as a key molecular factor in human health and its implication in diseases

“…According to a research, TFEB regulates a transcriptional program that favors ECM adhesion turnover by encouraging the transcription of genes that produce cholesterol, which, in turn, increases caveolin-1 aggregation and integrin 1 endocytosis that is caveolin dependent. 162 …”