%0 Journal Article
%T Organellar stress intersects the astrocyte endoplasmic reticulum, mitochondria and nucleolus in HIV associated neurodegeneration
%A Anuja Ghorpade
%A Shruthi Nooka
%J Archive of "Cell Death & Disease".
%D 2018
%R 10.1038/s41419-018-0341-3
%X Primary human astrocytes were treated with IL-1¦Â (20 ng/ml) and HIV-1 (p24, 20 ng/ml) alone or in combination (a) or with increasing concentrations of hydrogen peroxide (H2O2) (100£¿¦ÌM, 200£¿¦ÌM, and 400 ¦ÌM) (b, c) and untreated astrocytes were maintained in parallel. RNA was isolated (8£¿h) and RRS1 mRNA levels were analyzed by RT2-PCR. Total cell lysates were immunoblotted for RRS1 and GAPDH following 24£¿h. GAPDH was used as housekeeping and loading controls. A representative blot is presented, while the average fold change from multiple independent donors is graphed. Statistical analyses were performed using one-way ANOVA with Tukey¡¯s post-test for multiple comparisons (*p£¿<£¿0.05, **p£¿<£¿0.01, ***p£¿<£¿0.001). Data represent mean£¿¡À£¿standard error of the mean. d Astrocyte organelle stress responses during HAND (1) HIV-1 infected/activated CNS cells release HIV-1 proteins, ROS, and proinflammatory cytokines such as TNF-¦Á and IL-1¦Â. (2) Astrocytes become reactive in response to HIV-relevant stimuli. (3) Our data establish that IL-1¦Â- and ARV-mediated increases in intracellular calcium initiate ER stress and mitochondrial dysfunction. (4) Activation of the UPR pathways PERK, IRE1¦Á, and ATF6 result in expression of ER chaperones BiP and calnexin. (5) AEG-1 interaction with the calcium-binding chaperone calnexin suggests a role in calcium signaling. (6) HIV-1-relevant inflammation and oxidative stress significantly increase RRS1 expression, suggesting inhibition of rRNA transcription and nucleolar stress in astrocytes during HIV-1 infection. Taken together, we propose that the organelle network with interlinked stress responses may play a crucial role in HIV-associated neuropathogenesis and could be promising therapeutic targets in HAND. Scheme abbreviations: AEG-1 astrocyte elevated gene, ARV antiretroviral, ATF activating transcription factor, BiP binding immunoglobulin protein, Ca2+ calcium, ER endoplasmic reticulum, ERAD ER-associated degradation, f fragment, HIV human immunodeficiency virus, ROS reactive oxygen species, p-eIF phosphorylated-eukaryotic initiation factor, PERK protein kinase RNA-like ER kinase, IRE inositol-requiring enzyme, RRS regulator of ribosome synthesis, XBP x-box binding protei
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833429/