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- Title
Human Immunodeficiency Virus Type 1 (HIV-1) Transactivator of Transcription through Its Intact Core and Cysteine-Rich Domains Inhibits Wnt/ß-Catenin Signaling in Astrocytes: Relevance to HIV Neuropathogenesis.
- Authors
Henderson, Lisa J.; Sharma, Amit; Monaco, Maria Chiara G.; Major, Eugene O.; Al-Harthi, Lena
- Abstract
Wnt/ß-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/ß-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/ß-catenin signaling can compromise astrocyte function, we evaluated the impact of HIV transactivator of transcription (Tat) on Wnt/ß-catenin signaling in astrocytes. HIV clade Β Tat, in primary progenitor-derived astrocytes and U87MG cells, inhibited Wnt/ß-catenin signaling as demonstrated by its inhibition of active ß-catenin, TOPflash reporter activity, and Axin-2 (a downstream target of Wnt/ß-catenin signaling). Point mutations in either the core region (K41A) or the cysteine-rich region (C30G) of Tat abrogated its ability to inhibit ß-catenin signaling. Clade C Tat, which lacks the dicysteine motif, did not alter ß-catenin signaling, confirming that the dicysteine motif is critical for Tat inhibition of ß-catenin signaling. Tat coprecipitated with TCF-4 (a transcription factor that partners with ß-catenin), suggesting a physical interaction between these two proteins. Furthermore, knockdown of ß-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/ß-catenin that negatively impacts their cognate target genes. The consequences of this interaction include alleviation of Wnt/ß-catenin-mediated suppression of HIV and possible astrocyte dysregulation contributing to HIV neuropathogenesis.
- Subjects
HIV; IMMUNODEFICIENCY; GENETIC transcription; CYSTEINE; CATENINS; CELLULAR signal transduction; ASTROCYTES; CELLULAR control mechanisms; CELL physiology
- Publication
Journal of Neuroscience, 2012, Vol 32, Issue 46, p16306
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.3145-12.2012