title: 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.
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.
authors.affiliation: Department of Immunology/Microbiology, Rush University Medical Center, Chicago, Illinois 60612, USA.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Henderson
authors.forename: Amit
authors.initials: A
authors.lastname: Sharma
authors.forename: Maria Chiara G
authors.initials: MC
authors.lastname: Monaco
authors.forename: Eugene O
authors.initials: EO
authors.lastname: Major
authors.forename: Lena
authors.initials: L
authors.lastname: Al-Harthi
mesh_terms: D015526:AIDS Dementia Complex / Q000473:pathology*; D001253:Astrocytes / Q000502:physiology*; D015153:Blotting, Western; D002460:Cell Line; D003545:Cysteine / Q000502:physiology; D005434:Flow Cytometry; D015696:Gene Products, tat / Q000502:physiology; D017930:Genes, Reporter / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D017354:Point Mutation / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D051153:Wnt Proteins / Q000037:antagonists & inhibitors*; D051176:beta Catenin / Q000037:antagonists & inhibitors*; D054321:rev Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics / Q000502:physiology*
chemical_list: D015696:Gene Products, tat; D051153:Wnt Proteins; D051176:beta Catenin; D054321:rev Gene Products, Human Immunodeficiency Virus; D018698:Glutamic Acid; D008156:Luciferases; D003545:Cysteine