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J Neurosci. 2012 Nov 14;32(46):16306-13. doi: 10.1523/JNEUROSCI.3145-12.2012.

Human immunodeficiency virus type 1 (HIV-1) transactivator of transcription through its intact core and cysteine-rich domains inhibits Wnt/β-catenin signaling in astrocytes: relevance to HIV neuropathogenesis.

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  • 1Department of Immunology/Microbiology, Rush University Medical Center, Chicago, Illinois 60612, USA.

Abstract

Wnt/β-catenin is a neuroprotective pathway regulating cell fate commitment in the CNS and many vital functions of neurons and glia. Its dysregulation is linked to a number of neurodegenerative diseases. Wnt/β-catenin is also a repressor of HIV transcription in multiple cell types, including astrocytes, which are dysregulated in HIV-associated neurocognitive disorder. Given that HIV proteins can overcome host restriction factors and that perturbations of Wnt/β-catenin signaling can compromise astrocyte function, we evaluated the impact of HIV transactivator of transcription (Tat) on Wnt/β-catenin signaling in astrocytes. HIV clade B Tat, in primary progenitor-derived astrocytes and U87MG cells, inhibited Wnt/β-catenin signaling as demonstrated by its inhibition of active β-catenin, TOPflash reporter activity, and Axin-2 (a downstream target of Wnt/β-catenin signaling). Point mutations in either the core region (K41A) or the cysteine-rich region (C30G) of Tat abrogated its ability to inhibit β-catenin signaling. Clade C Tat, which lacks the dicysteine motif, did not alter β-catenin signaling, confirming that the dicysteine motif is critical for Tat inhibition of β-catenin signaling. Tat coprecipitated with TCF-4 (a transcription factor that partners with β-catenin), suggesting a physical interaction between these two proteins. Furthermore, knockdown of β-catenin or TCF-4 enhanced docking of Tat at the TAR region of the HIV long terminal repeat. These findings highlight a bidirectional interference between Tat and Wnt/β-catenin that negatively impacts their cognate target genes. The consequences of this interaction include alleviation of Wnt/β-catenin-mediated suppression of HIV and possible astrocyte dysregulation contributing to HIV neuropathogenesis.

PMID:
23152614
[PubMed - indexed for MEDLINE]
PMCID:
PMC3508723
Free PMC Article
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