HIV-1 Nef interacts with inositol trisphosphate receptor to activate calcium signaling in T cells.
HIV-1 pathogenicity factor Nef has been shown to modulate calcium signaling in host cells, but the underlying molecular mechanisms have remained unclear. Here we show that calcium/calcineurin-dependent activation of nuclear factor of activated T cells (NFAT) by Nef in Jurkat T cells requires the endoplasmic reticulum-resident inositol trisphosphate receptor (IP(3)R), but yet does not involve increase in phospholipase-C gamma 1 (PLC gamma 1)-catalyzed production of IP(3) or depletion of IP(3)-regulated intracellular calcium stores. Nef could be coprecipitated with endogenous IP(3)R type-1 (IP(3)R1) from Nef-transfected Jurkat T cells as well as from HIV-infected primary human peripheral mononuclear cells. Thus, the Nef/IP(3)R1-interaction defines a novel T cell receptor-independent mechanism by which Nef can promote T cell activation, and appears to involve atypical IP(3)R-triggered activation of plasma membrane calcium influx channels in a manner that is uncoupled from depletion of intracellular calcium stores.
Manninen
Aki
A
Institute of Medical Technology, University of Tampere, Tampere FIN-33014, Finland.
Saksela
Kalle
K
D021581:Active Transport, Cell Nucleus; D002118:Calcium / Q000276:immunology; D015220:Calcium Channels / Q000276:immunology*; D020013:Calcium Signaling / Q000276:immunology*; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000276:immunology; D004268:DNA-Binding Proteins / Q000276:immunology; D015693:Gene Products, nef / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007527:Isoenzymes / Q000276:immunology; D019169:Jurkat Cells; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D051966:Phospholipase C gamma; D018160:Receptors, Cytoplasmic and Nuclear / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014157:Transcription Factors / Q000276:immunology; D010738:Type C Phospholipases / Q000276:immunology; D054311:nef Gene Products, Human Immunodeficiency Virus
D015220:Calcium Channels; D004268:DNA-Binding Proteins; D015693:Gene Products, nef; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007527:Isoenzymes; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D054311:nef Gene Products, Human Immunodeficiency Virus; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D002118:Calcium