CD95/phosphorylated ezrin association underlies HIV-1 GP120/IL-2-induced susceptibility to CD95(APO-1/Fas)-mediated apoptosis of human resting CD4(+)T lymphocytes.
CD95(APO-1/Fas)-mediated apoptosis of bystander uninfected T cells exerts a major role in the HIV-1-mediated CD4+ T-cell depletion. HIV-1 gp120 has a key role in the induction of sensitivity of human lymphocytes to CD95-mediated apoptosis through its interaction with the CD4 receptor. Recently, we have shown the importance of CD95/ezrin/actin association in CD95-mediated apoptosis. In this study, we explored the hypothesis that the gp120-mediated CD4 engagement could be involved in the induction of susceptibility of primary human T lymphocytes to CD95-mediated apoptosis through ezrin phosphorylation and ezrin-to-CD95 association. Here, we show that gp120/IL-2 combined stimuli, as well as the direct CD4 triggering, on human primary CD4(+)T lymphocytes induced an early and stable ezrin activation through phosphorylation, consistent with the induction of ezrin/CD95 association and susceptibility to CD95-mediated apoptosis. Our results provide a new mechanism through which HIV-1-gp120 may predispose resting CD4(+)T cell to bystander CD95-mediated apoptosis and support the key role of ezrin/CD95 linkage in regulating susceptibility to CD95-mediated apoptosis.
Luciani
F
F
Laboratories of Immunology, Istituto Superiore di Sanità, 00161 Rome, Italy.
Matarrese
P
P
Giammarioli
A M
AM
Lugini
L
L
Lozupone
F
F
Federici
C
C
Iessi
E
E
Malorni
W
W
Fais
S
S
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015704:CD4 Antigens / Q000378:metabolism; D003598:Cytoskeletal Proteins; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D013601:T-Lymphocytes / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*; D000099149:Ezrin
D015704:CD4 Antigens; D003598:Cytoskeletal Proteins; D015699:HIV Envelope Protein gp120; D007376:Interleukin-2; D010750:Phosphoproteins; D019014:fas Receptor; D000099149:Ezrin