Gatekeeper role of 14-3-3tau protein in HIV-1 gp120-mediated apoptosis of human endothelial cells by inactivation of Bad.
OBJECTIVE
HIV-1-associated dementia (HAD) is a major neurological complication often observed in the advanced stages of AIDS. We have reported that 14-3-3 proteins in cerebrospinal fluid, reflecting neuronal cell destruction, is a real-time marker of HAD progression. This study was designed to examine the role of 14-3-3 proteins in HAD.


METHODS
An in-vitro human umbilical vein endothelial cells (HUVEC) model of gp120 protein-induced apoptosis to study the protective role of 14-3-3 in HIV-1 gp120/CXCR4-mediated cell death.


METHODS
The alpha-chemokine receptor-mediated cell death by HIV-1 envelope protein, gp120, the critical event that causes neuron loss and endothelial cell injury, was evaluated in HUVEC undergoing gp120-induced apoptosis through the CXCR4 receptor. We studied the effects of siRNA for each 14-3-3 isoform on the death of HUVEC treated with CXCR4-preferring gp120 (IIIB).


RESULTS
Gp120 increased the expression of 14-3-3tau in HUVEC. The binding of Gp120 to CXCR4 induced apoptosis of HUVEC through decreased binding of 14-3-3tau to the pro-apoptotic molecule, Bad. Treatment of the cells with dsRNA against 14-3-3tau enhanced the gp120-mediated dephosphorylation of Bad and its association with Bcl-XL in mitochondria, accelerating the gp120-induced apoptosis, whereas suppression of Bad by RNAi rescued the cells from apoptosis triggered by gp120.


CONCLUSIONS
The specific up-regulation of 14-3-3tau in HUVEC negatively regulated gp120/CXCR4-mediated cell death by protecting Bad dephosphorylation.
Yano
Mihiro
M
Division of Enzyme Chemistry, Institute for Enzyme Research, The University of Tokushima, Tokushima 770-8503, Japan.
Nakamuta
Shinichi
S
Shiota
Mayumi
M
Endo
Hiroshi
H
Kido
Hiroshi
H
D048948:14-3-3 Proteins / Q000096:biosynthesis / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology* / Q000502:physiology; D019302:HIV Envelope Protein gp160 / Q000494:pharmacology; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014178:Translocation, Genetic; D015854:Up-Regulation / Q000187:drug effects; D051025:bcl-Associated Death Protein / Q000378:metabolism / Q000502:physiology*
D048948:14-3-3 Proteins; D015699:HIV Envelope Protein gp120; D019302:HIV Envelope Protein gp160; D011994:Recombinant Proteins; D051025:bcl-Associated Death Protein; D045304:Cytochromes c