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.