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Molecular Pharmacology

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Research ArticleArticle

Dysregulation of Endoplasmic Reticulum Stress and Autophagic Responses by the Antiretroviral Drug Efavirenz

Luc Bertrand and Michal Toborek
Molecular Pharmacology August 2015, 88 (2) 304-315; DOI: https://doi.org/10.1124/mol.115.098590
Luc Bertrand
Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, Miami, Florida
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Michal Toborek
Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, Miami, Florida
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Abstract

Increasing evidence demonstrates that the antiretroviral drugs (ARVds) used for human immunodeficiency virus (HIV) treatment have toxic effects that result in various cellular and tissue pathologies; however, their impact on the cells composing the blood-brain barrier is poorly understood. The current study focused on ARVds, used either in combination or alone, on the induction of endoplasmic reticulum (ER) stress responses in human brain endothelial cells. Among studied drugs (efavirenz, tenofovir, emtricitabine, lamivudine, and indinavir), only efavirenz increased ER stress via upregulation and activation of protein kinase-like ER kinase PERK and inositol requiring kinase 1α (IRE1α). At the same time, efavirenz diminished autophagic activity, a surprising result because typically the induction of ER stress is linked to enhanced autophagy. These results were confirmed in microvessels of HIV transgenic mice chronically administered with efavirenz. In a series of further experiments, we identified that efavirenz dysregulated ER stress and autophagy by blocking the activity of the Beclin-1/Atg14/PI3KIII complex in regard to synthesis of phosphatidylinositol 3-phosphate, a process that is linked to the formation of autophagosomes. Because autophagy is a protective mechanism involved in the removal of dysfunctional proteins and organelles, its inhibition can contribute to the toxicity of efavirenz or the development of neurodegenerative disease in HIV patients treated with this drug.

Footnotes

    • Received February 21, 2015.
    • Accepted May 15, 2015.
  • This work was supported by the National Institutes of Health [Grants R01-MH098891, R01-MH072567, R01-MH063022, R01-HL126559, R01-DA039576, and R01-DA027569].

  • dx.doi.org/10.1124/mol.115.098590.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 88 (2)
Molecular Pharmacology
Vol. 88, Issue 2
1 Aug 2015
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Research ArticleArticle

Dysregulation of ER Stress and Autophagy by Efavirenz

Luc Bertrand and Michal Toborek
Molecular Pharmacology August 1, 2015, 88 (2) 304-315; DOI: https://doi.org/10.1124/mol.115.098590

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Research ArticleArticle

Dysregulation of ER Stress and Autophagy by Efavirenz

Luc Bertrand and Michal Toborek
Molecular Pharmacology August 1, 2015, 88 (2) 304-315; DOI: https://doi.org/10.1124/mol.115.098590
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