title: Bacterial DNA Protects Monocytic Cells against HIV-Vpr-Induced Mitochondrial Membrane Depolarization.
abstract: Monocytes and macrophages are important HIV reservoirs, as they exhibit marked resistance to apoptosis upon infection. However, the mechanism underlying resistance to apoptosis in these cells is poorly understood. Using HIV-viral protein R-52-96 aa peptide (Vpr), we show that primary monocytes and THP-1 cells treated with Vpr are highly susceptible to mitochondrial depolarization, but develop resistance following stimulation with bacterial DNA or CpG oligodeoxynucleotide. We have shown that Vpr-induced mitochondrial depolarization is mediated by TNFR-associated factor-1 (TRAF-1) and TRAF-2 degradation and subsequent activation of caspase-8, Bid, and Bax. To provide the mechanism governing such resistance to mitochondrial depolarization, our results show that prior stimulation with CpG oligodeoxynucleotide or Escherichia coli DNA prevented: 1) TRAF-1/2 downregulation; 2) activation of caspase-8, Bid, and Bax; and 3) subsequent mitochondrial depolarization and release of apoptosis-inducing factor and cytochrome c Furthermore, this protection was mediated by upregulation of antiapoptotic protein (c-IAP-2) through calmodulin-dependent kinase-II activation. Thus, c-IAP-2 may prevent Vpr-mediated mitochondrial depolarization through stabilizing TRAF-1/2 expression and sequential inhibition of caspase-8, Bid, and Bax.
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada;
authors.forename: Mansi
authors.initials: M
authors.lastname: Saxena
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada;
authors.forename: Aurelia
authors.initials: A
authors.lastname: Busca
authors.affiliation: Research Institute, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada; and.
authors.forename: Martin
authors.initials: M
authors.lastname: Holcik
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada; Research Institute, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada; and Department of Pathology and Laboratory Medicine, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada akumar@uottawa.ca.
authors.forename: Ashok
authors.identifier: 0000-0002-3615-8681
authors.initials: A
authors.lastname: Kumar
mesh_terms: D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002460:Cell Line; D004269:DNA, Bacterial / Q000276:immunology*; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology*; D053078:Membrane Potential, Mitochondrial; D009000:Monocytes / Q000276:immunology*; D047990:TNF Receptor-Associated Factor 1 / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: C494826:BAX protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D004269:DNA, Bacterial; D051034:Inhibitor of Apoptosis Proteins; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D051028:bcl-2-Associated X Protein; D054325:vpr Gene Products, Human Immunodeficiency Virus; C514912:vpr protein, Human immunodeficiency virus 1; D053181:Caspase 8