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Mononuclear phagocytes (MP, macrophages and microglia), the main targets of HIV-1 infection in the brain, play a pathogenic role in HIV-associated neurocognitive disorders (HAND) through the production and release of various soluble neurotoxic factors including glutamate. We have previously reported that glutaminase (GLS), the glutamate-generating enzyme, is upregulated in HIV-1 infected MP and in the brain tissues of HIV dementia individuals, and that HIV-1 or interferon-α (IFN-α) regulates human  glutaminase 1  ( GLS1 ) promoter through signal transducer and activator of transcription 1 (STAT1) phosphorylation in macrophages. However, there are multiple putative STAT1 binding sites in human  GLS1  promoter, the exact molecular mechanism of how HIV-1 or IFN-α regulates human  GLS1  promoter remains unclear. To further study the function of the putative STAT1 binding sites, we mutated the sequence of each binding site to  ACTAGTCTC  and found that six mutants (mut 1,3,4,5,7,8) had significantly higher promoter activity and two mutants (mut 2 and mut 6) completely lost the promoter activity compared with the wild type. To determine whether sites 2 and 6 could interfere with other inhibitory sites, particularly the nearby inhibitory sites 3 and 5, we made double mutants dmut 2/3 and dmut 5/6, and found that both the double mutants had significantly higher activity than the wild type, indicating that sites 3 and 5 are critical inhibitory elements, while sites 2 and 6 are excitatory elements. ChIP assay verified that STAT1 could bind with sites 2/3 and 5/6 within human  GLS1  promoter in IFN-α stimulated or HIV-1-infected monocyte-derived macrophages. Interestingly, we found that rat  Gls1  promoter was regulated through a similar way as human  GLS1  promoter. Together, our data identified critical elements that regulate  GLS1  promoter activity.

STAT1 Regulates Human Glutaminase 1 Promoter Activity through Multiple Binding Sites in HIV-1 Infected Macrophages