title: HIV-1 Vpr triggers mitochondrial destruction by impairing Mfn2-mediated ER-mitochondria interaction.
abstract: 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.
authors.affiliation: Graduate Institute of Microbiology and Public Health, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Huang
authors.forename: Shu-Fen
authors.initials: SF
authors.lastname: Chiang
authors.forename: Tze-Yi
authors.initials: TY
authors.lastname: Lin
authors.forename: Shiow-Her
authors.initials: SH
authors.lastname: Chiou
authors.forename: Kuan-Chih
authors.initials: KC
authors.lastname: Chow
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D002460:Cell Line; D034281:Dynamins; D004721:Endoplasmic Reticulum / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D015497:HIV-1 / Q000378:metabolism* / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions / Q000502:physiology; D006801:Humans; D008561:Membrane Fusion; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010539:Permeability; D021381:Protein Transport; D059008:Time-Lapse Imaging; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D054325:vpr Gene Products, Human Immunodeficiency Virus; C514912:vpr protein, Human immunodeficiency virus 1; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; C110768:DNM1L protein, human; D034281:Dynamins