Phosphatidylinositol-(4,5)-bisphosphate enables efficient secretion of HIV-1 Tat by infected T-cells

Fabienne Rayne, Solène Debaisieux, Hocine Yezid, Yea Lih Lin, Clément Mettling, Karidia Konate, Nathalie Chazal, Stefan T. Arold, Martine Pugnière, Françoise Sanchez, Anne Bonhoure, Laurence Briant, Erwann Loret, Christian Roy, Bruno Beaumelle*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

119 Scopus citations

Abstract

Human immunodeficiency virus type 1 (HIV-1) transcription relies on its transactivating Tat protein. Although devoid of a signal sequence, Tat is released by infected cells and secreted Tat can affect uninfected cells, thereby contributing to HIV-1 pathogenesis. The mechanism and the efficiency of Tat export remained to be documented. Here, we show that, in HIV-1-infected primary CD4 T-cells that are the main targets of the virus, Tat accumulates at the plasma membrane because of its specific binding to phosphatidylinositol-4,5- bisphosphate (PI(4,5)P 2). This interaction is driven by a specific motif of the Tat basic domain that recognizes a single PI(4,5)P 2 molecule and is stabilized by membrane insertion of Tat tryptophan side chain. This original recognition mechanism enables binding to membrane-embedded PI(4,5)P 2 only, but with an unusually high affinity that allows Tat to perturb the PI(4,5)P 2-mediated recruitment of cellular proteins. Tat-PI(4,5)P 2 interaction is strictly required for Tat secretion, a process that is very efficient, as 2/3 of Tat are exported by HIV-1-infected cells during their lifespan. The function of extracellular Tat in HIV-1 infection might thus be more significant than earlier thought.

Original languageEnglish (US)
Pages (from-to)1348-1362
Number of pages15
JournalEMBO Journal
Volume29
Issue number8
DOIs
StatePublished - Apr 1 2010

Keywords

  • HIV-1
  • PIP2
  • Tat
  • Toxin
  • Unconventional secretion

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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