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J Biol Chem. 2014 Jul 11;289(28):19599-612. doi: 10.1074/jbc.M114.567644. Epub 2014 May 22.

Astrocyte elevated gene-1 is a novel modulator of HIV-1-associated neuroinflammation via regulation of nuclear factor-κB signaling and excitatory amino acid transporter-2 repression.

Author information

1
From the Department of Cell Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas 76107 and.
2
the Departments of Pathology and Neuroscience & Cell Biology, University of Texas Medical Branch, Galveston, Texas 77555.
3
From the Department of Cell Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas 76107 and Anuja.Ghorpade@unthsc.edu.

Abstract

Astrocyte elevated gene-1 (AEG-1), a novel human immunodeficiency virus (HIV)-1 and tumor necrosis factor (TNF)-α-inducible oncogene, has generated significant interest in the field of cancer research as a therapeutic target for many metastatic aggressive tumors. However, little is known about its role in astrocyte responses during HIV-1 central nervous system (CNS) infection and whether it contributes toward the development of HIV-associated neurocognitive disorders (HAND). Therefore, in this study, we investigated changes in AEG-1 CNS expression in HIV-1-infected brain tissues and elucidated a potential mechanism of AEG-1-mediated regulation of HAND. Immunoblotting and immunohistochemical analyses of HIV-1 seropositive and HIV-1 encephalitic human brain tissues revealed significantly elevated levels of AEG-1 protein. Immunohistochemical analyses of HIV-1 Tat transgenic mouse brain tissues also showed a marked increase in AEG-1 staining. Similar to in vivo observations, cultured astrocytes expressing HIV-1 Tat also revealed AEG-1 and cytokine up-regulation. Astrocytes treated with HAND-relevant stimuli, TNF-α, interleukin (IL)-1β, and HIV-1, also significantly induced AEG-1 expression and nuclear translocation via activation of the nuclear factor (NF)-κB pathway. Co-immunoprecipitation studies demonstrated IL-1β- or TNF-α-induced AEG-1 interaction with NF-κB p65 subunit. AEG-1 knockdown decreased NF-κB activation, nuclear translocation, and transcriptional output in TNF-α-treated astrocytes. Moreover, IL-1β treatment of AEG-1-overexpressing astrocytes significantly lowered expression of excitatory amino acid transporter 2, increased expression of excitatory amino acid transporter 2 repressor ying yang 1, and reduced glutamate clearance, a major transducer of excitotoxic neuronal damage. Findings from this study identify a novel transcriptional co-factor function of AEG-1 and further implicate AEG-1 in HAND-associated neuroinflammation.

KEYWORDS:

AEG-1; Astrocyte; Cancer; HIV-1-associated Neurocognitive Disorders; Human Immunodeficiency Virus (HIV); Neurodegeneration; Neuroinflammation

PMID:
24855648
PMCID:
PMC4094071
DOI:
10.1074/jbc.M114.567644
[Indexed for MEDLINE]
Free PMC Article

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