Directed Expression of the HIV-1 Accessory Protein Vpu in Drosophila Fat-body Cells Inhibits Toll-dependent Immune Responses

Overview

Journal EMBO Rep

Specialty Molecular Biology

Date 2003 Sep 16

PMID 12973300

Citations 27

Authors

Francois Leulier

Christelle Marchal

Isabelle Miletich

Bernadette Limbourg-Bouchon

Richard Benarous

Bruno Lemaitre

Affiliations

Soon will be listed here.

Abstract

Human immunodeficiency virus 1 (HIV-1) expresses several accessory proteins that manipulate various host-cell processes to achieve optimum replicative efficiency. One of them, viral protein U (Vpu), has been shown to interfere with the cellular degradation machinery through interaction with SCF(beta-TrCP) complexes. To learn more about Vpu function in vivo, we used the genetically tractable fruit fly, Drosophila melanogaster. Our results show that the directed expression of Vpu, but not the non-phosphorylated form, Vpu2/6, in fat-body cells affects Drosophila antimicrobial responses. In flies, the Toll and Imd pathways regulate antimicrobial-peptide gene expression. We show that Vpu specifically affects Toll pathway activation by inhibiting Cactus degradation. Given the conservation of the Toll/nuclear factor-kappa B (NF-kappa B) signalling pathways between flies and mammals, our results suggest a function for Vpu in the inhibition of host NF-kappa B-mediated innate immune defences and provide a powerful genetic approach for studying Vpu inhibition of NF-kappa B signalling in vivo.

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References

Karin M, Ben-Neriah Y . Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol. 2000; 18:621-63. DOI: 10.1146/annurev.immunol.18.1.621. View

Tauszig S, Jouanguy E, Hoffmann J, Imler J . Toll-related receptors and the control of antimicrobial peptide expression in Drosophila. Proc Natl Acad Sci U S A. 2000; 97(19):10520-5. PMC: 27057. DOI: 10.1073/pnas.180130797. View

Silverman N, Zhou R, Stoven S, Pandey N, Hultmark D, Maniatis T . A Drosophila IkappaB kinase complex required for Relish cleavage and antibacterial immunity. Genes Dev. 2000; 14(19):2461-71. PMC: 316979. DOI: 10.1101/gad.817800. View

Heissmeyer V, Krappmann D, Hatada E, Scheidereit C . Shared pathways of IkappaB kinase-induced SCF(betaTrCP)-mediated ubiquitination and degradation for the NF-kappaB precursor p105 and IkappaBalpha. Mol Cell Biol. 2001; 21(4):1024-35. PMC: 99557. DOI: 10.1128/MCB.21.4.1024-1035.2001. View

Stoven S, Ando I, Kadalayil L, Engstrom Y, Hultmark D . Activation of the Drosophila NF-kappaB factor Relish by rapid endoproteolytic cleavage. EMBO Rep. 2001; 1(4):347-52. PMC: 1083746. DOI: 10.1093/embo-reports/kvd072. View

Leulier F, Rodriguez A, Khush R, Abrams J, Lemaitre B . The Drosophila caspase Dredd is required to resist gram-negative bacterial infection. EMBO Rep. 2001; 1(4):353-8. PMC: 1083747. DOI: 10.1093/embo-reports/kvd073. View

Bour S, Perrin C, Akari H, Strebel K . The human immunodeficiency virus type 1 Vpu protein inhibits NF-kappa B activation by interfering with beta TrCP-mediated degradation of Ikappa B. J Biol Chem. 2001; 276(19):15920-8. DOI: 10.1074/jbc.M010533200. View

Alexopoulou L, Holt A, Medzhitov R, Flavell R . Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 2001; 413(6857):732-8. DOI: 10.1038/35099560. View

Akari H, Bour S, Kao S, Adachi A, Strebel K . The human immunodeficiency virus type 1 accessory protein Vpu induces apoptosis by suppressing the nuclear factor kappaB-dependent expression of antiapoptotic factors. J Exp Med. 2001; 194(9):1299-311. PMC: 2195969. DOI: 10.1084/jem.194.9.1299. View

10.

Tauszig-Delamasure S, Bilak H, Capovilla M, Hoffmann J, Imler J . Drosophila MyD88 is required for the response to fungal and Gram-positive bacterial infections. Nat Immunol. 2001; 3(1):91-7. DOI: 10.1038/ni747. View

11.

Fong A, Sun S . Genetic evidence for the essential role of beta-transducin repeat-containing protein in the inducible processing of NF-kappa B2/p100. J Biol Chem. 2002; 277(25):22111-4. DOI: 10.1074/jbc.C200151200. View

12.

Doyle S, Vaidya S, OConnell R, Dadgostar H, Dempsey P, Wu T . IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity. 2002; 17(3):251-63. DOI: 10.1016/s1074-7613(02)00390-4. View

13.

Hultmark D . Drosophila immunity: paths and patterns. Curr Opin Immunol. 2002; 15(1):12-9. DOI: 10.1016/s0952-7915(02)00005-5. View

14.

Stoven S, Silverman N, Junell A, Hedengren-Olcott M, Erturk D, Engstrom Y . Caspase-mediated processing of the Drosophila NF-kappaB factor Relish. Proc Natl Acad Sci U S A. 2003; 100(10):5991-6. PMC: 156314. DOI: 10.1073/pnas.1035902100. View

15.

Galindo R, EDWARDS D, Gillespie S, Wasserman S . Interaction of the pelle kinase with the membrane-associated protein tube is required for transduction of the dorsoventral signal in Drosophila embryos. Development. 1995; 121(7):2209-18. DOI: 10.1242/dev.121.7.2209. View

16.

Lemaitre B, Nicolas E, Michaut L, Reichhart J, Hoffmann J . The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell. 1996; 86(6):973-83. DOI: 10.1016/s0092-8674(00)80172-5. View

17.

Dushay M, Asling B, Hultmark D . Origins of immunity: Relish, a compound Rel-like gene in the antibacterial defense of Drosophila. Proc Natl Acad Sci U S A. 1996; 93(19):10343-7. PMC: 38386. DOI: 10.1073/pnas.93.19.10343. View

18.

Reach M, Galindo R, Towb P, Allen J, Karin M, Wasserman S . A gradient of cactus protein degradation establishes dorsoventral polarity in the Drosophila embryo. Dev Biol. 1996; 180(1):353-64. DOI: 10.1006/dbio.1996.0308. View

19.

Belvin M, Anderson K . A conserved signaling pathway: the Drosophila toll-dorsal pathway. Annu Rev Cell Dev Biol. 1996; 12:393-416. DOI: 10.1146/annurev.cellbio.12.1.393. View

20.

Jiang J, Struhl G . Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb. Nature. 1998; 391(6666):493-6. DOI: 10.1038/35154. View