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.
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.
From the Department of Cell Biology and Immunology, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, Texas 76107.
Yan
Y
Fan
From the Department of Cell Biology and Immunology, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, Texas 76107 johnny.he@unthsc.edu.
Johnny J
http://orcid.org/0000-0002-0837-4889
JJ
He
D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D020258:Neurotoxicity Syndromes / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010654:Phenylbutyrates / Q000494:pharmacology; D066263:Protein Aggregation, Pathological / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D056811:Unfolded Protein Response; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
D005904:Glial Fibrillary Acidic Protein; D010654:Phenylbutyrates; C528900:glial fibrillary astrocytic protein, mouse; D054322:tat Gene Products, Human Immunodeficiency Virus; C075773:4-phenylbutyric acid
Glial fibrillary acidic protein; HIV-1 Tat; astrocytes; endoplasmic reticulum stress; endoplasmic reticulum stress (ER stress); glial cell; human immunodeficiency virus (HIV); neuron; unfolded protein response; unfolded protein response (UPR)