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Vol. 15, Issue 5, 2347-2360, May 2004
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UMR 5539 CNRS, Département Biologie-Santé, Case 107, Université Montpellier II, 34095 Montpellier Cedex 5, France
Submitted December 23, 2003;
Revised February 19, 2004;
Accepted February 20, 2004
Monitoring Editor: Howard Riezman
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 after 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.
Abbreviations used: Baf, bafilomycin; CQ, chloroquine; CNF1, cytotoxic necrotizing factor 1; DT, diphtheria toxin; FACS, fluorescence-activated cell sorting; FCS, fetal calf serum; HRP, horseradish peroxidase; LDL, low-density lipoproteins; LBPA, lysobisphosphatidic acid; LRP, LDL receptor-related protein; LTR, long terminal repeat; mAb, monoclonal antibody; M6PR, mannose 6-phosphate receptor; PTD, protein transduction domain; Tf, transferrin.
Corresponding author. E-mail address: beaumel{at}univ-montp2.fr.
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