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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • AIDS Dementia Complex / genetics
  • AIDS Dementia Complex / metabolism*
  • AIDS Dementia Complex / pathology
  • Animals
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Brain / metabolism
  • Brain / pathology
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • Down-Regulation / genetics
  • Excitatory Amino Acid Transporter 2 / genetics
  • Excitatory Amino Acid Transporter 2 / metabolism*
  • Female
  • Glutamate Plasma Membrane Transport Proteins / genetics
  • Glutamate Plasma Membrane Transport Proteins / metabolism*
  • Glutamic Acid / genetics
  • Glutamic Acid / metabolism
  • HIV-1 / genetics
  • HIV-1 / metabolism*
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / pathology
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Membrane Proteins
  • Mice
  • Mice, Transgenic
  • RNA-Binding Proteins
  • Signal Transduction*
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism*
  • YY1 Transcription Factor / genetics
  • YY1 Transcription Factor / metabolism
  • tat Gene Products, Human Immunodeficiency Virus / genetics
  • tat Gene Products, Human Immunodeficiency Virus / metabolism

Substances

  • Cell Adhesion Molecules
  • Crisp1 protein, mouse
  • Excitatory Amino Acid Transporter 2
  • Glutamate Plasma Membrane Transport Proteins
  • IL1B protein, human
  • IL1B protein, mouse
  • Interleukin-1beta
  • MTDH protein, human
  • Membrane Glycoproteins
  • Membrane Proteins
  • RELA protein, human
  • RNA-Binding Proteins
  • Rela protein, mouse
  • SLC1A2 protein, human
  • Slc1a2 protein, mouse
  • Transcription Factor RelA
  • YY1 Transcription Factor
  • YY1 protein, human
  • tat Gene Products, Human Immunodeficiency Virus
  • Glutamic Acid