Journal Article

HIV-1 Tat and Heparan Sulfate Proteoglycans Orchestrate the Setup of in Cis and in Trans Cell-Surface Interactions Functional to Lymphocyte Trans-Endothelial Migration

Urbinati, Chiara, D’Ursi, Pasqualina, Rusnati, Marco, Milanesi, Maria, Lauro, Nicola, David, Guido, Chiodelli, Paola, Bertelli, Cinzia

2021

Overview

HIV-1 transactivating factor Tat is released by infected cells. Extracellular Tat homodimerizes and engages several receptors, including integrins, vascular endothelial growth factor receptor 2 (VEGFR2) and heparan sulfate proteoglycan (HSPG) syndecan-1 expressed on various cells. By means of experimental cell models recapitulating the processes of lymphocyte trans-endothelial migration, here, we demonstrate that upon association with syndecan-1 expressed on lymphocytes, Tat triggers simultaneously the in cis activation of lymphocytes themselves and the in trans activation of endothelial cells (ECs). This “two-way” activation eventually induces lymphocyte adhesion and spreading onto the substrate and vascular endothelial (VE)-cadherin reorganization at the EC junctions, with consequent endothelial permeabilization, leading to an increased extravasation of Tat-presenting lymphocytes. By means of a panel of biochemical activation assays and specific synthetic inhibitors, we demonstrate that during the above-mentioned processes, syndecan-1, integrins, FAK, src and ERK1/2 engagement and activation are needed in the lymphocytes, while VEGFR2, integrin, src and ERK1/2 are needed in the endothelium. In conclusion, the Tat/syndecan-1 complex plays a central role in orchestrating the setup of the various in cis and in trans multimeric complexes at the EC/lymphocyte interface. Thus, by means of computational molecular modelling, docking and dynamics, we also provide a characterization at an atomic level of the binding modes of the Tat/heparin interaction, with heparin herein used as a structural analogue of the heparan sulfate chains of syndecan-1.

• Publisher: MDPI AG,MDPI
• Subject: Acquired immune deficiency syndrome / AIDS / Cell Adhesion / Cell adhesion & migration / Cell Movement / Chemokines / Cytoskeleton / endothelial cells / Endothelium / Endothelium - chemistry / Endothelium - metabolism / Heparan sulfate / heparan sulfate proteoglycans / Heparan Sulfate Proteoglycans - chemistry / Heparan Sulfate Proteoglycans - metabolism / HIV / HIV-1 Tat / Human immunodeficiency virus / Humans / integrins / Kinases / Ligands / Lipids / lymphocyte extravasation / Lymphocytes / Lymphocytes - chemistry / Lymphocytes - metabolism / Lymphoma / Models, Molecular / Molecular Structure / Proteins / signal transduction / Stereoisomerism / tat Gene Products, Human Immunodeficiency Virus - chemistry / tat Gene Products, Human Immunodeficiency Virus - metabolism / Tumor Cells, Cultured