title: Role of β-catenin and TCF/LEF family members in transcriptional activity of HIV in astrocytes.
abstract: The Wnt/β-catenin pathway is involved in diverse cell functions governing development and disease. β-Catenin, a central mediator of this pathway, binds to members of the TCF/LEF family of transcription factors to modulate hundreds of genes. Active Wnt/β-catenin/TCF-4 signaling plays a significant role in repression of HIV-1 replication in multiple cell targets, including astrocytes. To determine the mechanism by which active β-catenin/TCF-4 leads to inhibition of HIV replication, we knocked down β-catenin or TCF/LEF members in primary astrocytes and astrocytomas transiently transfected with an HIV long terminal repeat (LTR)-luciferase reporter that contained an integrated copy of the HIV LTR-luciferase construct. Knockdown of either β-catenin or TCF-4 induced LTR activity by 2- to 3-fold under both the episomal and integrated conditions. This knockdown also increased presence of serine 2-phosphorylated RNA polymerase II (Pol II) on the HIV LTR as well as enhanced its processivity. Knockdown of β-catenin/TCF-4 also impacted tethering of other transcription factors on the HIV promoter. Specifically, knockdown of TCF-4 enhanced binding of C/EBPβ, C/EBPδ, and NF-κB to the HIV LTR, while β-catenin knockdown increased binding of C/EBPβ and C/EBPδ but had no effect on NF-κB. Approximately 150 genes in astrocytes were impacted by β-catenin knockdown, including genes involved in inflammation/immunity, uptake/transport, vesicular transport/exocytosis, apoptosis/cellular stress, and cytoskeleton/trafficking. These findings indicate that modulation of the β-catenin/TCF-4 axis impacts the basal level of HIV transcription in astrocytes, which may drive low level/persistent HIV in astrocytes that can contribute to ongoing neuroinflammation, and this axis also has profound effects on astrocyte biology.
authors.affiliation: Department of Immunology/Microbiology, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Srinivas D
authors.initials: SD
authors.lastname: Narasipura
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Henderson
authors.forename: Sidney W
authors.initials: SW
authors.lastname: Fu
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.forename: Fatah
authors.initials: F
authors.lastname: Kashanchi
authors.forename: Lena
authors.initials: L
authors.lastname: Al-Harthi
mesh_terms: D001253:Astrocytes / Q000378:metabolism* / Q000821:virology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015967:Gene Expression Regulation, Viral; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D015398:Signal Transduction; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin