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HIV-1 Tat induces unfolded protein response and endoplasmic reticulum stress in astrocytes and causes neurotoxicity through GFAP activation and aggregation.

HIV-1 Tat induces unfolded protein response and endoplasmic reticulum stress in astrocytes and causes neurotoxicity through GFAP activation and aggregation.
Author Information (click to view)

Fan Y, He JJ,


Fan Y, He JJ, (click to view)

Fan Y, He JJ,

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The Journal of biological chemistry 2016 9 8() pii

Abstract

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 indispensible 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 unfold 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 chemical chaperone 4-phenylbutyrate significantly alleviated astrocyte-mediated Tat neurotoxicity in vitro and in the brain of Tat-expressing mice. Taken together, these results showed that HIV-1 Tat expression led to UPR/ER stress in astrocytes, which in turn contributed to astrocyte-mediated Tat neurotoxicity and raise the possibility of developing HIV/neuroAIDS therapeutics targeted at UPR/ER stress.

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