title: The HIV-1 Vpu protein induces apoptosis in Drosophila via activation of JNK signaling.
abstract: The genome of the human immunodeficiency virus type 1 (HIV-1) encodes the canonical retroviral proteins, as well as additional accessory proteins that enhance the expression of viral genes, the infectivity of the virus and the production of virions. The accessory Viral Protein U (Vpu), in particular, enhances viral particle production, while also promoting apoptosis of HIV-infected human T lymphocytes. Some Vpu effects rely on its interaction with the ubiquitin-proteasome protein degradation system, but the mechanisms responsible for its pro-apoptotic effects in vivo are complex and remain largely to be elucidated.We took advantage of the Drosophila model to study the effects of Vpu activity in vivo. Expression of Vpu in the developing Drosophila wing provoked tissue loss due to caspase-dependent apoptosis. Moreover, Vpu induced expression of the pro-apoptotic gene reaper, known to down-regulate Inhibitor of Apoptosis Proteins (IAPs) which are caspase-antagonizing E3 ubiquitin ligases. Indeed, Vpu also reduced accumulation of Drosophila IAP1 (DIAP1). Though our results demonstrate a physical interaction between Vpu and the proteasome-addressing SLIMB/β-TrCP protein, as in mammals, both SLIMB/βTrCP-dependent and -independent Vpu effects were observed in the Drosophila wing. Lastly, the pro-apoptotic effect of Vpu in this tissue was abrogated upon inactivation of the c-Jun N-terminal Kinase (JNK) pathway. Our results in the fly thus provide the first functional evidence linking Vpu pro-apoptotic effects to activation of the conserved JNK pathway.
authors.affiliation: Laboratoire de Génétique et Biologie Cellulaire, EA4589, Université de Versailles St-Quentin-en-Yvelines, Versailles, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Marchal
authors.forename: Gérald
authors.initials: G
authors.lastname: Vinatier
authors.forename: Matthieu
authors.initials: M
authors.lastname: Sanial
authors.forename: Anne
authors.initials: A
authors.lastname: Plessis
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Pret
authors.forename: Bernadette
authors.initials: B
authors.lastname: Limbourg-Bouchon
authors.forename: Laurent
authors.initials: L
authors.lastname: Théodore
authors.forename: Sophie
authors.initials: S
authors.lastname: Netter
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D004331:Drosophila melanogaster; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D015967:Gene Expression Regulation, Viral; D015497:HIV-1 / Q000378:metabolism*; D054298:Human Immunodeficiency Virus Proteins / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction; D019076:Transgenes; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism*; D014921:Wings, Animal / Q000378:metabolism; D000086082:Viroporin Proteins
chemical_list: D020169:Caspases; D054298:Human Immunodeficiency Virus Proteins; D048670:MAP Kinase Kinase 4; D054334:Viral Regulatory and Accessory Proteins; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins