HIV-1 tat interactions with p300 and PCAF transcriptional coactivators inhibit histone acetylation and neurotrophin signaling through CREB

Kasuen Wong, Anima Sharma, Soumya Awasthi, Elizabeth F. Matlock, Lowery Rogers, Carine Van Lint, Daniel J. Skiest, Dennis K. Burns, Robert Harrod

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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 trans-activation 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.

Original languageEnglish (US)
Pages (from-to)9390-9399
Number of pages10
JournalJournal of Biological Chemistry
Volume280
Issue number10
DOIs
StatePublished - Mar 11 2005

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Acetylation
Nerve Growth Factors
Viruses
Histones
HIV-1
Neurology
Central Nervous System
Nerve Growth Factor
Apoptosis
Acquired Immunodeficiency Syndrome
Human Immunodeficiency Virus tat Gene Products
Chemical activation
CREB-Binding Protein
trkB Receptor
Nerve Growth Factor Receptors
Histone Acetyltransferases
Nerve Growth Factor Receptor
Nerve Tissue
Fluorescence Resonance Energy Transfer
Viral Antigens

ASJC Scopus subject areas

  • Biochemistry

Cite this

HIV-1 tat interactions with p300 and PCAF transcriptional coactivators inhibit histone acetylation and neurotrophin signaling through CREB. / Wong, Kasuen; Sharma, Anima; Awasthi, Soumya; Matlock, Elizabeth F.; Rogers, Lowery; Van Lint, Carine; Skiest, Daniel J.; Burns, Dennis K.; Harrod, Robert.

In: Journal of Biological Chemistry, Vol. 280, No. 10, 11.03.2005, p. 9390-9399.

Research output: Contribution to journalArticle

Wong, Kasuen ; Sharma, Anima ; Awasthi, Soumya ; Matlock, Elizabeth F. ; Rogers, Lowery ; Van Lint, Carine ; Skiest, Daniel J. ; Burns, Dennis K. ; Harrod, Robert. / HIV-1 tat interactions with p300 and PCAF transcriptional coactivators inhibit histone acetylation and neurotrophin signaling through CREB. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 10. pp. 9390-9399.
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AU - Wong, Kasuen

AU - Sharma, Anima

AU - Awasthi, Soumya

AU - Matlock, Elizabeth F.

AU - Rogers, Lowery

AU - Van Lint, Carine

AU - Skiest, Daniel J.

AU - Burns, Dennis K.

AU - Harrod, Robert

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AB - 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 trans-activation 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.

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