Abstract Title

Astrocyte AEG-1 regulates ER stress responses in the context of HAND

RAD Assignment Number

1511

Presenter Name

Shruthi Nooka

Abstract

Endoplasmic reticulum (ER) stress has recently been linked to neurological disorders, including HIV-associated neurocognitive disorders (HAND). We recently showed astrocyte elevated gene (AEG)-1, a multifunctional oncogene regulating astrocyte migration, proliferation and neuroinflammation. AEG-1 upregulation in Huntington’s disease model suggests its role in ER stress responses in aging and HAND. However, its involvement in ER stress responses during HIV-1 infection is not known. In this study, we investigated HIV-1 and anti-retroviral therapy (ART) drugs mediated ER stress i.e., unfolded protein response (UPR) pathway activation, and astrocyte AEG-1 expression, intracellular localization during ER stress. RT-PCR and western blot analysis revealed that HIV-1, IL-1β and ART drugs activated UPR pathway and autophagy in astrocytes. Moreover, astrocytes exposed to ER stress compounds upregulated AEG-1 expression. Confocal analysis and mPTP assay showed AEG-1 colocalization with calnexin and mitochondrial damage with ER stress. In addition, AEG-1 overexpression upregulated ER stress markers such as BiP, PERK, and CHOP that were further enhanced by IL-1β treatment. Immunocytochemical studies also showed increased autophagy markers i.e., LC3 and P62 in AEG-1 overexpressing astrocytes. In summary, our study highlights that HIV-infection and ART drugs induce ER stress in astrocytes that is further exacerbated by AEG-1. Therefore, elucidation of AEG-1 regulated UPR pathway could assist in targeting astrocyte-induced ER stress responses in HAND.

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Astrocyte AEG-1 regulates ER stress responses in the context of HAND

Endoplasmic reticulum (ER) stress has recently been linked to neurological disorders, including HIV-associated neurocognitive disorders (HAND). We recently showed astrocyte elevated gene (AEG)-1, a multifunctional oncogene regulating astrocyte migration, proliferation and neuroinflammation. AEG-1 upregulation in Huntington’s disease model suggests its role in ER stress responses in aging and HAND. However, its involvement in ER stress responses during HIV-1 infection is not known. In this study, we investigated HIV-1 and anti-retroviral therapy (ART) drugs mediated ER stress i.e., unfolded protein response (UPR) pathway activation, and astrocyte AEG-1 expression, intracellular localization during ER stress. RT-PCR and western blot analysis revealed that HIV-1, IL-1β and ART drugs activated UPR pathway and autophagy in astrocytes. Moreover, astrocytes exposed to ER stress compounds upregulated AEG-1 expression. Confocal analysis and mPTP assay showed AEG-1 colocalization with calnexin and mitochondrial damage with ER stress. In addition, AEG-1 overexpression upregulated ER stress markers such as BiP, PERK, and CHOP that were further enhanced by IL-1β treatment. Immunocytochemical studies also showed increased autophagy markers i.e., LC3 and P62 in AEG-1 overexpressing astrocytes. In summary, our study highlights that HIV-infection and ART drugs induce ER stress in astrocytes that is further exacerbated by AEG-1. Therefore, elucidation of AEG-1 regulated UPR pathway could assist in targeting astrocyte-induced ER stress responses in HAND.