HIV-1 Tat Interactions with p300 and PCAF Transcriptional Coactivators Inhibit Histone Acetylation and Neurotrophin Signaling through CREB

• Published in: The Journal of biological chemistry Vol. 280; no. 10; pp. 9390 - 9399
• Main Authors: Wong, Kasuen, Sharma, Anima, Awasthi, Soumya, Matlock, Elizabeth F., Rogers, Lowery, Van Lint, Carine, Skiest, Daniel J., Burns, Dennis K., Harrod, Robert
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.03.2005; American Society for Biochemistry and Molecular Biology
• Subjects: Acetylation; Acetyltransferases - metabolism; Amino Acid Sequence; Animals; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cyclic AMP Response Element-Binding Protein - physiology; Fluorescence Resonance Energy Transfer; Gene Products, tat - metabolism; Histone Acetyltransferases; Histones - metabolism; HIV-1 - physiology; Human immunodeficiency virus 1; Humans; Microscopy, Confocal; Molecular Sequence Data; Nerve Growth Factors - physiology; Neuroblastoma; p300-CBP Transcription Factors; PC12 Cells; Pheochromocytoma; Rats; Recombinant Fusion Proteins - isolation & purification; Recombinant Fusion Proteins - metabolism; Signal Transduction; tat Gene Products, Human Immunodeficiency Virus; Transcription Factors - metabolism; Transfection; Virus Replication
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M408643200

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.