HIV-1 Tat Induces Unfolded Protein Response and Endoplasmic Reticulum Stress in Astrocytes and Causes Neurotoxicity through Glial Fibrillary Acidic Protein (GFAP) Activation and Aggregation

• Published in: The Journal of biological chemistry 2016-10, Vol.291 (43), p.22819-22829
• Main Authors: Fan, Yan, He, Johnny J.
• Format: Article
• Language: English
• Subjects: Animals; astrocytes; Astrocytes - metabolism; Astrocytes - pathology; Brain - metabolism; Brain - pathology; Cell Line, Tumor; Endoplasmic Reticulum Stress; endoplasmic reticulum stress (ER stress); glial cell; Glial fibrillary acidic protein; Glial Fibrillary Acidic Protein - metabolism; HIV-1 - genetics; HIV-1 - metabolism; HIV-1 Tat; human immunodeficiency virus (HIV); Humans; Mice; Mice, Transgenic; Molecular Bases of Disease; neuron; Neurotoxicity Syndromes - drug therapy; Neurotoxicity Syndromes - genetics; Neurotoxicity Syndromes - metabolism; Neurotoxicity Syndromes - pathology; Phenylbutyrates - pharmacology; Protein Aggregation, Pathological - drug therapy; Protein Aggregation, Pathological - genetics; Protein Aggregation, Pathological - metabolism; Protein Aggregation, Pathological - pathology; tat Gene Products, Human Immunodeficiency Virus - genetics; tat Gene Products, Human Immunodeficiency Virus - metabolism; Unfolded Protein Response; unfolded protein response (UPR)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M116.731828

HIV-1 Tat is a major culprit for HIV/neuroAIDS. One of the consistent hallmarks of HIV/neuroAIDS is reactive astrocytes or astrocytosis, characterized by increased cytoplasmic accumulation of the intermediate filament glial fibrillary acidic protein (GFAP). We have shown that that Tat induces GFAP expression in astrocytes and that GFAP activation is indispensable for astrocyte-mediated Tat neurotoxicity. However, the underlying molecular mechanisms are not known. In this study, we showed that Tat expression or GFAP expression led to formation of GFAP aggregates and induction of unfolded protein response (UPR) and endoplasmic reticulum (ER) stress in astrocytes. In addition, we demonstrated that GFAP up-regulation and aggregation in astrocytes were necessary but also sufficient for UPR/ER stress induction in Tat-expressing astrocytes and for astrocyte-mediated Tat neurotoxicity. Importantly, we demonstrated that inhibition of Tat- or GFAP-induced UPR/ER stress by the chemical chaperone 4-phenylbutyrate significantly alleviated astrocyte-mediated Tat neurotoxicity in vitro and in the brain of Tat-expressing mice. Taken together, these results show that HIV-1 Tat expression leads to UPR/ER stress in astrocytes, which in turn contributes to astrocyte-mediated Tat neurotoxicity, and raise the possibility of developing HIV/neuroAIDS therapeutics targeted at UPR/ER stress.