title: 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.
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.
authors.affiliation: From the Department of Cell Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas 76107 and.
authors.forename: Neha
authors.initials: N
authors.lastname: Vartak-Sharma
authors.affiliation: the Departments of Pathology and Neuroscience & Cell Biology, University of Texas Medical Branch, Galveston, Texas 77555.
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Gelman
authors.affiliation: From the Department of Cell Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas 76107 and.
authors.forename: Chaitanya
authors.initials: C
authors.lastname: Joshi
authors.affiliation: From the Department of Cell Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas 76107 and.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Borgamann
authors.affiliation: From the Department of Cell Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas 76107 and Anuja.Ghorpade@unthsc.edu.
authors.forename: Anuja
authors.initials: A
authors.lastname: Ghorpade
mesh_terms: D015526:AIDS Dementia Complex / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D050491:Glutamate Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D016601:RNA-Binding Proteins; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D050986:YY1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; C486321:Crisp1 protein, mouse; D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; C508585:IL1B protein, human; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; C483039:MTDH protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C498143:RELA protein, human; D016601:RNA-Binding Proteins; C498144:Rela protein, mouse; C493397:SLC1A2 protein, human; C493396:Slc1a2 protein, mouse; D051996:Transcription Factor RelA; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; D054322:tat Gene Products, Human Immunodeficiency Virus; D018698:Glutamic Acid
keywords: AEG-1; Astrocyte; Cancer; HIV-1-associated Neurocognitive Disorders; Human Immunodeficiency Virus (HIV); Neurodegeneration; Neuroinflammation