HIV-1 associated neurocognitive disorders (HAND) develop during progressive HIV-1 infection and affect up to 50% of infected individuals. Activated microglia and macrophages are critical cell populations that are involved in the pathogenesis of HAND, which is specifically related to the production and release of various soluble neurotoxic factors including glutamate. In the central nervous system (CNS), glutamate is typically derived from glutamine by mitochondrial enzyme glutaminase. Our previous study has shown that glutaminase is upregulated in HIV-1 infected monocyte-derived-macrophages (MDM) and microglia. However, how HIV-1 leads to glutaminase upregulation, or how glutaminase expression is regulated in general, remains unclear. In this study, using a dual-luciferase reporter assay system, we demonstrated that interferon (IFN) α specifically activated the glutaminase 1 (GLS1) promoter. Furthermore, IFN-α treatment increased signal transducer and activator of transcription 1 (STAT1) phosphorylation and glutaminase mRNA and protein levels. IFN-α stimulation of GLS1 promoter activity correlated to STAT1 phosphorylation and was reduced by fludarabine, a chemical that inhibits STAT1 phosphorylation. Interestingly, STAT1 was found to directly bind to the GLS1 promoter in MDM, an effect that was dependent on STAT1 phosphorylation and significantly enhanced by IFN-α treatment. More importantly, HIV-1 infection increased STAT1 phosphorylation and STAT1 binding to the GLS1 promoter, which was associated with increased glutamate levels. The clinical relevance of these findings was further corroborated with investigation of post-mortem brain tissues. The glutaminase C (GAC, one isoform of GLS1) mRNA levels in HIV associated-dementia (HAD) individuals correlate with STAT1 (p
AIDS Dementia Complex, Animals, Base Sequence, Brain, Cells, Cultured, Dose-Response Relationship, Drug, Gene Expression Regulation, Glutamic Acid, Glutaminase, HEK293 Cells, HIV Infections, HIV-1, Host-Pathogen Interactions, Humans, Interferon-alpha, Isoenzymes, Macrophages, Molecular Sequence Data, Monocytes, Phosphorylation, Promoter Regions, Genetic, Protein Binding, Rats, Reverse Transcriptase Polymerase Chain Reaction, STAT1 Transcription Factor
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Zhao, Lixia; Huang, Yunlong; Tian, Changhai; Taylor, Lynn; Curthoys, Norman; Wang, Yi; Vernon, Hamilton; and Zheng, Jialin C., "Interferon-α regulates glutaminase 1 promoter through STAT1 phosphorylation: relevance to HIV-1 associated neurocognitive disorders." (2012). Journal Articles: Pharmacology & Experimental Neuroscience. 44.