Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus
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Calcium / immunology
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Calcium Channels / immunology*
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Calcium Signaling / immunology*
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Cell Line, Transformed
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Cell Nucleus / immunology
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DNA-Binding Proteins / immunology
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Gene Products, nef / genetics
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Gene Products, nef / immunology*
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HIV-1 / genetics
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HIV-1 / immunology*
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Humans
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Inositol 1,4,5-Trisphosphate Receptors
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Isoenzymes / immunology
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Jurkat Cells
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NFATC Transcription Factors
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Nuclear Proteins*
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Phospholipase C gamma
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Receptors, Cytoplasmic and Nuclear / immunology*
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T-Lymphocytes / immunology*
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Transcription Factors / immunology
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Type C Phospholipases / immunology
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nef Gene Products, Human Immunodeficiency Virus
Substances
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Calcium Channels
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DNA-Binding Proteins
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Gene Products, nef
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ITPR1 protein, human
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Inositol 1,4,5-Trisphosphate Receptors
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Isoenzymes
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NFATC Transcription Factors
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Nuclear Proteins
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Receptors, Cytoplasmic and Nuclear
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Transcription Factors
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nef Gene Products, Human Immunodeficiency Virus
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Type C Phospholipases
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Phospholipase C gamma
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Calcium