Journal Article

HIV-1 Vpr Triggers Mitochondrial Destruction by Impairing Mfn2-Mediated ER-Mitochondria Interaction

Huang, Chih-Yang, Chow, Kuan-Chih, Chiang, Shu-Fen, Chiou, Shiow-Her, Lin, Tze-Yi

2012

Overview

Human immunodeficiency virus 1 (HIV-1) viral protein R (Vpr) has been shown to induce host cell death by increasing the permeability of mitochondrial outer membrane (MOM). The mechanism underlying the damage to the mitochondria by Vpr, however, is not clearly illustrated. In this study, Vpr that is introduced, via transient transfection or lentivirus infection, into the human embryonic kidney cell line HEK293, human CD4(+) T lymphoblast cell line SupT1, or human primary CD4(+) T cells serves as the model system to study the molecular mechanism of Vpr-mediated HIV-1 pathogenesis. The results show that Vpr injures MOM and causes a loss in membrane potential (MMP) by posttranscriptionally reducing the expression of mitofusin 2 (Mfn2) via VprBP-DDB1-CUL4A ubiquitin ligase complex, gradually weakening MOM, and increasing mitochondrial deformation. Vpr also markedly decreases cytoplasmic levels of dynamin-related protein 1 (DRP1) and increases bulging in mitochondria-associated membranes (MAM), the specific regions of endoplasmic reticulum (ER) which form physical contacts with the mitochondria. Overexpression of Mfn2 and DRP1 significantly decreased the loss of MMP and apoptotic cell death caused by Vpr. Furthermore, by employing time-lapse confocal fluorescence microscopy, we identify the transport of Vpr protein from the ER, via MAM to the mitochondria. Taken together, our results suggest that Vpr-mediated cellular damage may occur on an alternative protein transport pathway from the ER, via MAM to the mitochondria, which are modulated by Mfn2 and DRP1.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Amino acids / Apoptosis / Biology / CD4 antigen / CD4-Positive T-Lymphocytes - metabolism / CD4-Positive T-Lymphocytes - pathology / CD4-Positive T-Lymphocytes - virology / Cell cycle / Cell death / Cell Line / Cytomegalovirus / Deformation / Deformation mechanisms / Dynamin / Endoplasmic reticulum / Endoplasmic Reticulum - metabolism / Fibroblasts / Fluorescence / Fluorescence microscopy / Gene Knockdown Techniques / GTP Phosphohydrolases - antagonists & inhibitors / GTP Phosphohydrolases - genetics / GTP Phosphohydrolases - metabolism / Health aspects / HEK293 Cells / Hepatitis / HIV / HIV-1 - metabolism / HIV-1 - pathogenicity / Host-Pathogen Interactions - physiology / Human immunodeficiency virus / Humans / Infection / Infections / Lung cancer / Lymphocytes / Lymphocytes T / Medicine / Membrane Fusion / Membrane permeability / Membrane potential / Membranes / Microscopy, Confocal / Microscopy, Electron, Transmission / Microtubule-Associated Proteins - antagonists & inhibitors / Microtubule-Associated Proteins - genetics / Microtubule-Associated Proteins - metabolism / Mitochondria / Mitochondria - metabolism / Mitochondria - pathology / Mitochondrial Membranes - metabolism / Mitochondrial Membranes - pathology / Mitochondrial Proteins - antagonists & inhibitors / Mitochondrial Proteins - genetics / Mitochondrial Proteins - metabolism / Neutrophils / Pathogenesis / Permeability / Protein Transport / Proteins / Public health / T cells / Time-Lapse Imaging / Transfection / Ubiquitin / Ubiquitin-protein ligase / Utrophin / Viral proteins / Viruses / vpr Gene Products, Human Immunodeficiency Virus - metabolism / Vpr protein