HIV-1 Tat-mediated activation of glycogen synthase kinase-3beta contributes to Tat-mediated neurotoxicity.
Human immunodeficiency virus type 1 (HIV-1) Tat induces neuronal apoptosis. To examine the mechanism(s) that contribute to this process, we studied Tat's effects on glycogen synthase kinase-3beta (GSK-3beta), an enzyme that has been implicated in the regulation of apoptosis. Addition of Tat to rat cerebellar granule neurons resulted in an increase in GSK-3beta activity, which was not associated with a change in protein expression and could be abolished by the addition of an inhibitor of GSK-3beta (lithium). Lithium also enhanced neuronal survival following exposure to Tat. Coprecipitation experiments revealed that Tat can associate with GSK-3beta, but direct addition of Tat to purified GSK-3beta had no effect on enzyme activity, suggesting that Tat's effects might be mediated indirectly. As the activation of platelet activating factor (PAF) receptors is critical for the induction of neuronal death by several candidate HIV-1 neurotoxins, we determined whether PAF can also activate GSK-3beta. Application of PAF to neuronal cultures activated GSK-3beta, and coincubation with lithium ameliorated PAF-induced neuronal apoptosis. These findings are consistent with the existence of one or more pathways that can lead to GSK-3beta activation in neurons, and they suggest that the dysregulation of this enzyme could contribute to HIV-induced neuronal apoptosis.
Maggirwar
S B
SB
Department of Microbiology and Immunology, University of Rochester Medical Center, New York 14642, USA.
Tong
N
N
Ramirez
S
S
Gelbard
H A
HA
Dewhurst
S
S
D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology; D001381:Azepines / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D015696:Gene Products, tat / Q000378:metabolism / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D015497:HIV-1; D018021:Lithium Chloride / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000201:enzymology* / Q000821:virology*; D009498:Neurotoxins / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D054322:tat Gene Products, Human Immunodeficiency Virus
D018692:Antimanic Agents; D001381:Azepines; D018690:Excitatory Amino Acid Agonists; D015696:Gene Products, tat; D009498:Neurotoxins; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D011994:Recombinant Proteins; D014230:Triazoles; D054322:tat Gene Products, Human Immunodeficiency Virus; C052518:WEB 2086; D016202:N-Methylaspartate; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride