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J Biol Chem. 2015 Oct 16;290(42):25439-51. doi: 10.1074/jbc.M115.652776. Epub 2015 Sep 1.

A Novel Role of Proline Oxidase in HIV-1 Envelope Glycoprotein-induced Neuronal Autophagy.

Author information

1
From the Center for AIDS Health Disparities Research, School of Graduate Studies and Research, Department of Microbiology and Immunology, and jpandhare@mmc.edu.
2
From the Center for AIDS Health Disparities Research, School of Graduate Studies and Research.
3
From the Center for AIDS Health Disparities Research, School of Graduate Studies and Research, Department of Microbiology and Immunology, and.
4
From the Center for AIDS Health Disparities Research, School of Graduate Studies and Research, Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, Tennessee 37208.

Abstract

Proline oxidase (POX) catalytically converts proline to pyrroline-5-carboxylate. This catabolic conversion generates reactive oxygen species (ROS) that triggers cellular signaling cascades including autophagy and apoptosis. This study for the first time demonstrates a role of POX in HIV-1 envelope glycoprotein (gp120)-induced neuronal autophagy. HIV-1 gp120 is a neurotoxic factor and is involved in HIV-1-associated neurological disorders. However, the mechanism of gp120-mediated neurotoxicity remains unclear. Using SH-SY5Y neuroblastoma cells as a model, this study demonstrates that gp120 treatment induced POX expression and catalytic activity. Concurrently, gp120 also increased intracellular ROS levels. However, increased ROS had a minimal effect on neuronal apoptosis. Further investigation indicated that the immediate cellular response to increased ROS paralleled with induction of autophagy markers, beclin-1 and LC3-II. These data lead to the hypothesis that neuronal autophagy is activated as a cellular protective response to the toxic effects of gp120. A direct and functional role of POX in gp120-mediated neuronal autophagy was examined by inhibition and overexpression studies. Inhibition of POX activity by a competitive inhibitor "dehydroproline" decreased ROS levels concomitant with reduced neuronal autophagy. Conversely, overexpression of POX in neuronal cells increased ROS levels and activated ROS-dependent autophagy. Mechanistic studies suggest that gp120 induces POX by targeting p53. Luciferase reporter assays confirm that p53 drives POX transcription. Furthermore, data demonstrate that gp120 induces p53 via binding to the CXCR4 co-receptor. Collectively, these results demonstrate a novel role of POX as a stress response metabolic regulator in HIV-1 gp120-associated neuronal autophagy.

KEYWORDS:

autophagy; glycoprotein; human immunodeficiency virus (HIV); hydroxyproline; mitochondria; neuron; oxidative stress; reactive oxygen species (ROS)

PMID:
26330555
PMCID:
PMC4646191
DOI:
10.1074/jbc.M115.652776
[Indexed for MEDLINE]
Free PMC Article

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