HIV-1 Tat interactions with p300 and PCAF transcriptional coactivators inhibit histone acetylation and neurotrophin signaling through CREB.
The human immunodeficiency virus type-1 (HIV-1) infects microglia, macrophages, and astrocytes in the central nervous system (CNS) and may cause severe neurological diseases, such as AIDS-related dementias or progressive encephalopathies, as a result of CNS inflammation and neurotrophin signaling defects associated with expression of viral antigens and HIV-1 replication in ... the brain. The HIV Tat protein can be endocytosed by surrounding uninfected cells; interacts with transcriptional coactivators/acetyltransferases, p300/CREB-binding protein, and p300/CREB-binding protein-associated factor (PCAF); and induces neuronal apoptosis. Since nerve growth factor (NGF) receptor and brain-derived neurotrophic factor receptor signaling through CREB requires p300 and PCAF histone acetyltransferases, we sought to determine whether HIV-1 Tat coactivator interactions interfere with neurotrophin receptor signaling in neuronal cells. Here, we demonstrate that Tat-coactivator interactions inhibit NGF- and brain-derived neurotrophic factor-responsive CRE trans-activation and neurotrophin protection against apoptosis in PC12 and IMR-32 neuroblastoma cells. Purified recombinant Tat or Tat-derived synthetic peptides, spanning p300- and PCAF-binding sequences, inhibit histone H3/H4 acetylation in vitro. A Tat mutant, TatK28A/K50A, defective for binding p300 and PCAF, neither repressed NGF-responsive CRE transactivation nor inhibited histone acetylation. HIV-1 Tat interacts in PCAF complexes in post-mortem CNS tissues from donor neuro-AIDS patients, as determined by fluorescence resonance energy transfer immunoconfocal microscopy. Importantly, these findings suggest that HIV-1 Tat-coactivator interactions may contribute to neurotrophin signaling impairments and neuronal apoptosis associated with HIV-1 infections of the CNS.
Mesh Terms:
Acetylation, Acetyltransferases, Amino Acid Sequence, Animals, Cell Cycle Proteins, Cell Line, Tumor, Cyclic AMP Response Element-Binding Protein, Fluorescence Resonance Energy Transfer, Gene Products, tat, HIV-1, Histone Acetyltransferases, Histones, Humans, Microscopy, Confocal, Molecular Sequence Data, Nerve Growth Factors, Neuroblastoma, PC12 Cells, Pheochromocytoma, Rats, Recombinant Fusion Proteins, Signal Transduction, Transcription Factors, Transfection, Virus Replication, p300-CBP Transcription Factors, tat Gene Products, Human Immunodeficiency Virus
Acetylation, Acetyltransferases, Amino Acid Sequence, Animals, Cell Cycle Proteins, Cell Line, Tumor, Cyclic AMP Response Element-Binding Protein, Fluorescence Resonance Energy Transfer, Gene Products, tat, HIV-1, Histone Acetyltransferases, Histones, Humans, Microscopy, Confocal, Molecular Sequence Data, Nerve Growth Factors, Neuroblastoma, PC12 Cells, Pheochromocytoma, Rats, Recombinant Fusion Proteins, Signal Transduction, Transcription Factors, Transfection, Virus Replication, p300-CBP Transcription Factors, tat Gene Products, Human Immunodeficiency Virus
J. Biol. Chem.
Date: Mar. 11, 2005
PubMed ID: 15611041
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