期刊
MOLECULES
卷 26, 期 24, 页码 -出版社
MDPI
DOI: 10.3390/molecules26247488
关键词
HIV-1 Tat; heparan sulfate proteoglycans; lymphocyte extravasation; integrins; signal transduction; endothelial cells; molecular modelling docking and dynamics
资金
- Ministero dell'Istruzione, Universita e Ricerca (MIUR)
- EU Project EOSC-Pillar [857650]
Extracellular Tat released by HIV-infected cells engages with syndecan-1 on lymphocytes, triggering simultaneous activation of lymphocytes and endothelial cells. This two-way activation leads to lymphocyte adhesion, increased endothelial permeabilization, and enhanced extravasation of Tat-presenting lymphocytes. Activation of syndecan-1, integrins, FAK, src, and ERK1/2 in lymphocytes, as well as VEGFR2, integrin, src, and ERK1/2 in endothelium, is crucial in this process.
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.
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