Phosphatidylinositol-(4,5)-bisphosphate enables efficient secretion of HIV-1 Tat by infected T-cells.
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 approximately 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.
Rayne
Fabienne
F
CPBS, UMR 5236 CNRS, Case 100, Université Montpellier 2, Montpellier, France.
Debaisieux
Solène
S
Yezid
Hocine
H
Lin
Yea-Lih
YL
Mettling
Clément
C
Konate
Karidia
K
Chazal
Nathalie
N
Arold
Stefan T
ST
Pugnière
Martine
M
Sanchez
Françoise
F
Bonhoure
Anne
A
Briant
Laurence
L
Loret
Erwann
E
Roy
Christian
C
Beaumelle
Bruno
B
D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000821:virology*; D002462:Cell Membrane / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D015497:HIV-1 / Q000254:growth & development / Q000472:pathogenicity*; D006801:Humans; D019169:Jurkat Cells; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D011485:Protein Binding; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000032:analysis / Q000378:metabolism*
D019269:Phosphatidylinositol 4,5-Diphosphate; D054322:tat Gene Products, Human Immunodeficiency Virus