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A more recent version of this article appeared on May 1, 2004
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Submitted on December 23, 2003
Revised on February 19, 2004
Accepted on February 20, 2004
1 UMR 5539 CNRS, Département Biologie-Santé, Case 107, Université Montpellier II, 34095 Montpellier Cedex 5, France
* Corresponding author. E-mail address: beaumel{at}univ-montp2.fr.
The HIV-1 Tat protein is secreted by infected cells. Extracellular Tat can affect bystander uninfected T-cells and induce numerous biological responses such as apoptosis and cytokine secretion. Tat is likely involved in several immune disorders during AIDS. Nevertheless, it is not known whether Tat triggers cell responses directly upon binding to signaling receptors at the plasma membrane or following delivery to the cytosol. The pathway that enables Tat to reach the cytosol is also unclear. Here we visualized Tat within T-cell coated pits and endosomes. Moreover, inhibitors of clathrin/AP-2 mediated uptake such as chlorpromazine, activated RhoA, or dominant-negative mutants of Eps15, intersectin, dynamin or rab5 impaired Tat delivery to the cytosol by preventing its endocytosis. Molecules neutralizing low endosomal pH or Hsp90 inhibitors abolished Tat entry at a later stage by blocking its endosomal translocation, as directly shown using a cell-free translocation assay. Finally, endosomal pH neutralization prevented Tat from inducing T-cell responses such as NF-
B activation, apoptosis and interleukin secretion, indicating that cytosolic delivery is required for Tat signaling. Hence, Tat enters T-cells essentially like diphtheria toxin, using clathrin-mediated endocytosis before low-pH induced and Hsp90-assisted endosomal translocation. Cell responses are then induced from the cytosol.
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