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.

TitleAstrocyte 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.
Publication TypeJournal Article
Year of Publication2014
AuthorsVartak-Sharma, N, Gelman, BB, Joshi, C, Borgamann, K, Ghorpade, A
JournalJ Biol Chem
Volume289
Issue28
Pagination19599-612
Date Published2014 Jul 11
ISSN1083-351X
KeywordsAIDS Dementia Complex, Animals, Astrocytes, Brain, Cell Adhesion Molecules, Down-Regulation, Excitatory Amino Acid Transporter 2, External, Female, Glutamate Plasma Membrane Transport Proteins, Glutamic Acid, HIV-1, Humans, Inflammation, Interleukin-1beta, Male, Membrane Glycoproteins, Membrane Proteins, Mice, Mice, Transgenic, RNA-Binding Proteins, Signal Transduction, tat Gene Products, Human Immunodeficiency Virus, Transcription Factor RelA, YY1 Transcription Factor
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.

DOI10.1074/jbc.M114.567644
Alternate JournalJ Biol Chem
PubMed ID24855648
PubMed Central IDPMC4094071
Grant ListU01MH083500 / MH / NIMH NIH HHS / United States
U01 MH083507 / MH / NIMH NIH HHS / United States
R01 MH087345 / MH / NIMH NIH HHS / United States
R24 MH059724 / MH / NIMH NIH HHS / United States
U01 MH083500 / MH / NIMH NIH HHS / United States
5R24HD0008836 / HD / NICHD NIH HHS / United States
R01MH79886 / MH / NIMH NIH HHS / United States
U24 MH100928 / MH / NIMH NIH HHS / United States
R24 MH059745 / MH / NIMH NIH HHS / United States
R01 NS072005 / NS / NINDS NIH HHS / United States
R24 NS038841 / NS / NINDS NIH HHS / United States
R01MH087345 / MH / NIMH NIH HHS / United States
R24MH059724 / MH / NIMH NIH HHS / United States
R24NS038841 / NS / NINDS NIH HHS / United States
U01MH083501 / MH / NIMH NIH HHS / United States
R24NS045091 / NS / NINDS NIH HHS / United States
U01 MH083501 / MH / NIMH NIH HHS / United States
R24 HD000836 / HD / NICHD NIH HHS / United States
R01NS072005 / NS / NINDS NIH HHS / United States
U01MH083506 / MH / NIMH NIH HHS / United States
U01 MH083545 / MH / NIMH NIH HHS / United States
U01 MH083506 / MH / NIMH NIH HHS / United States
R01 MH079886 / MH / NIMH NIH HHS / United States
Z01 HD008836 / / Intramural NIH HHS / United States
U24 MH100930 / MH / NIMH NIH HHS / United States
U01MH083545 / MH / NIMH NIH HHS / United States
R01 NS045091 / NS / NINDS NIH HHS / United States