Interaction of Human Immunodeficiency Virus-1 Vpr and Glucocorticoid Receptor using Bimolecular Fluorescence Complementation (BiFC) analysis
Main Article Content
Abstract
Human Immunodeficiency Virus-1 Vpr, a nonstructural protein incorporated into virus particles, possesses several features contributing to virus replication and cytopathic effects. Vpr induced effects are mediated through its interactions with viral and/or host cellular proteins, in particular, the host protein, Glucocorticoid Receptor (GR). Though GR is known to increase Vpr-mediated HIV-1 transactivation, Vpr-GR interaction and its subcellular localization have not been studied in cells. Towards this, we evaluated Vpr interaction with GR in cells using Bimolecular Fluorescence Complementation analysis by generating chimeric Vpr or GR with the N- and C-terminal fragments of Venus protein. Our results showed that interaction between Vpr and GR requires certain Vpr and GR domains. Specifically, leucine residues in the third helical domain of Vpr and N-terminal domain of GR is involved in Vpr-GR interaction. Altering these residues not only interferes with Vpr-GR interaction, but also prevents translocation of this complex into the nucleus. Further, utilizing a mutant Vpr unable to oligomerize, we show that Vpr oligomerization is essential for optimal interaction with GR. In conclusion, by taking advantage of BiFC system, specific residues in Vpr have been found to be associated with binding GR and the subcellular distribution of Vpr-GR complex.
Keywords:
HIV-1, Vpr, Glucocorticoid Receptor, BiFC
Article Details
How to Cite
LI, Yaming et al.
Interaction of Human Immunodeficiency Virus-1 Vpr and Glucocorticoid Receptor using Bimolecular Fluorescence Complementation (BiFC) analysis.
Medical Research Archives, [S.l.], v. 10, n. 11, nov. 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3254>. Date accessed: 21 nov. 2024.
doi: https://doi.org/10.18103/mra.v10i11.3254.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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[47] Madan AP, DeFranco DB. Bidirectional transport of glucocorticoid receptors across the nuclear envelope. Proceedings of the National Academy of Sciences. 1993; 90(8):3588-92.
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[50] Nishi M, Kawata M. Dynamics of glucocorticoid receptor and mineralocorticoid receptor: implications from live cell imaging studies. Neuroendocrinology. 2007; 85(3):186-92.
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[53] Williams KC, Burdo TH. HIV and SIV infection: the role of cellular restriction and immune responses in viral replication and pathogenesis. APMIS. 2009; 117(5-6):400-12.
[54] Li G, Bukrinsky M, Zhao RY. HIV-1 viral protein R (Vpr) and its interactions with host cell. Curr HIV Res. 2009; 7(2):178-83.
[55] Ptak RG, Fu W, Sanders-Beer BE, et al. Cataloguing the HIV type 1 human protein interaction network. AIDS Res Hum Retroviruses. 2008; 24(12):1497-502.
[56] Busschots K, De Rijck J, Christ F, et al. In search of small molecules blocking interactions between HIV proteins and intracellular cofactors. Mol Biosyst. 2009; 5(1):21-31.
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[58] Iijima S, Nitahara-Kasahara Y, Kimata K, et al. Nuclear localization of Vpr is crucial for the efficient replication of HIV-1 in primary CD4+ T cells. Virology. 2004; 327(2):249-61.
[59] Sherman MP, de Noronha CM, Heusch MI, et al. Nucleocytoplasmic shuttling by human immunodeficiency virus type 1 Vpr. J Virol. 2001; 75(3):1522-32.
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[2] Connor RI, Chen BK, Choe S, et al. Vpr is required for efficient replication of human immunodeficiency virus type-1 in mononuclear phagocytes. Virology. 1995; 206(2):935-44.
[3] Freed EO, Englund G, Martin MA. Role of the basic domain of human immunodeficiency virus type 1 matrix in macrophage infection. J Virol. 1995; 69(6):3949-54.
[4] Subbramanian RA, Kessous-Elbaz A, Lodge R, et al. Human immunodeficiency virus type 1 Vpr is a positive regulator of viral transcription and infectivity in primary human macrophages. J Exp Med. 1998; 187(7):1103-11.
[5] Nitahara-Kasahara Y, Kamata M, Yamamoto T, et al. Novel nuclear import of Vpr promoted by importin alpha is crucial for human immunodeficiency virus type 1 replication in macrophages. J Virol. 2007; 81(10):5284-93.
[6] Agostini I, Popov S, Hao T, et al. Phosphorylation of Vpr regulates HIV type 1 nuclear import and macrophage infection. AIDS Res Hum Retroviruses. 2002; 18(4):283-8.
[7] Eckstein DA, Sherman MP, Penn ML, et al. HIV-1 Vpr enhances viral burden by facilitating infection of tissue macrophages but not nondividing CD4+ T cells. J Exp Med. 2001; 194(10):1407-19.
[8] Levy DN, Refaeli Y, MacGregor RR, et al. Serum Vpr regulates productive infection and latency of human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1994; 91(23):10873-7.
[9] Nakamura T, Suzuki H, Okamoto T, et al. Recombinant Vpr (rVpr) causes augmentation of HIV-1 p24 Ag level in U1 cells through its ability to induce the secretion of TNF. Virus Res. 2002; 90(1-2):263-8.
[10] McAllister JJ, Phillips D, Millhouse S, et al. Analysis of the HIV-1 LTR NF-kappaB-proximal Sp site III: evidence for cell type-specific gene regulation and viral replication. Virology. 2000; 274(2):262-77.
[11] Sawaya BE, Khalili K, Gordon J, et al. Cooperative interaction between HIV-1 regulatory proteins Tat and Vpr modulates transcription of the viral genome. J Biol Chem. 2000; 275(45):35209-14.
[12] Goh WC, Rogel ME, Kinsey CM, et al. HIV-1 Vpr increases viral expression by manipulation of the cell cycle: a mechanism for selection of Vpr in vivo. Nat Med. 1998; 4(1):65-71.
[13] Brass AL, Dykxhoorn DM, Benita Y, et al. Identification of host proteins required for HIV infection through a functional genomic screen. Science. 2008; 319(5865):921-6.
[14] Konig R, Zhou Y, Elleder D, et al. Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication. Cell. 2008; 135(1):49-60.
[15] Zhou H, Xu M, Huang Q, et al. Genome-scale RNAi screen for host factors required for HIV replication. Cell Host Microbe. 2008; 4(5):495-504.
[16] Somasundaran M, Sharkey M, Brichacek B, et al. Evidence for a cytopathogenicity determinant in HIV-1 Vpr. Proc Natl Acad Sci U S A. 2002; 99(14):9503-8.
[17] Zhao Y, Chen M, Wang B, et al. Functional conservation of HIV-1 Vpr and variability in a mother-child pair of long-term non-progressors. Virus Res. 2002; 89(1):103-21.
[18] Rodes B, Toro C, Paxinos E, et al. Differences in disease progression in a cohort of long-term non-progressors after more than 16 years of HIV-1 infection. AIDS. 2004; 18(8):1109-16.
[19] Richardson MW, Mirchandani J, Duong J, et al. Antibodies to Tat and Vpr in the GRIV cohort: differential association with maintenance of long-term non-progression status in HIV-1 infection. Biomed Pharmacother. 2003; 57(1):4-14.
[20] Cali L, Wang B, Mikhail M, et al. Evidence for host-driven selection of the HIV type 1 vpr gene in vivo during HIV disease progression in a transfusion-acquired cohort. AIDS Res Hum Retroviruses. 2005; 21(8):728-33.
[21] Henriet S, Mercenne G, Bernacchi S, et al. Tumultuous relationship between the human immunodeficiency virus type 1 viral infectivity factor (Vif) and the human APOBEC-3G and APOBEC-3F restriction factors. Microbiol Mol Biol Rev. 2009; 73(2):211-32.
[22] Sorin M, Yung E, Wu X, et al. HIV-1 replication in cell lines harboring INI1/hSNF5 mutations. Retrovirology. 2006; 3:56.
[23] Towers GJ. The control of viral infection by tripartite motif proteins and cyclophilin A. Retrovirology. 2007; 4:40.
[24] Kino T, Pavlakis GN. Partner molecules of accessory protein Vpr of the human immunodeficiency virus type 1. DNA Cell Biol. 2004; 23(4):193-205.
[25] Gragerov A, Kino T, Ilyina-Gragerova G, et al. HHR23A, the human homologue of the yeast repair protein RAD23, interacts specifically with Vpr protein and prevents cell cycle arrest but not the transcriptional effects of Vpr. Virology. 1998; 245(2):323-30.
[26] Le Rouzic E, Belaidouni N, Estrabaud E, et al. HIV1 Vpr arrests the cell cycle by recruiting DCAF1/VprBP, a receptor of the Cul4-DDB1 ubiquitin ligase. Cell Cycle. 2007; 6(2):182-8.
[27] Mahalingam S, Ayyavoo V, Patel M, et al. HIV-1 Vpr interacts with a human 34-kDa mov34 homologue, a cellular factor linked to the G2/M phase transition of the mammalian cell cycle. Proc Natl Acad Sci U S A. 1998; 95(7):3419-24.
[28] Sherman MP, de Noronha CM, Pearce D, et al. Human immunodeficiency virus type 1 Vpr contains two leucine-rich helices that mediate glucocorticoid receptor coactivation independently of its effects on G(2) cell cycle arrest. J Virol. 2000; 74(17):8159-65.
[29] Thotala D, Schafer EA, Tungaturthi PK, et al. Structure-functional analysis of human immunodeficiency virus type 1 (HIV-1) Vpr: role of leucine residues on Vpr-mediated transactivation and virus replication. Virology. 2004; 328(1):89-100.
[30] Hong H, Darimont BD, Ma H, et al. An additional region of coactivator GRIP1 required for interaction with the hormone-binding domains of a subset of nuclear receptors. J Biol Chem. 1999; 274(6):3496-502.
[31] Needham M, Raines S, McPheat J, et al. Differential interaction of steroid hormone receptors with LXXLL motifs in SRC-1a depends on residues flanking the motif. J Steroid Biochem Mol Biol. 2000; 72(1-2):35-46.
[32] Heitzer MD, Wolf IM, Sanchez ER, et al. Glucocorticoid receptor physiology. Rev Endocr Metab Disord. 2007; 8(4):321-30.
[33] Kino T, Stauber RH, Resau JH, et al. Pathologic human GR mutant has a transdominant negative effect on the wild-type GR by inhibiting its translocation into the nucleus: importance of the ligand-binding domain for intracellular GR trafficking. J Clin Endocrinol Metab. 2001; 86(11):5600-8.
[34] Kino T, Tsukamoto M, Chrousos G. Transcription factor TFIIH components enhance the GR coactivator activity but not the cell cycle-arresting activity of the human immunodeficiency virus type-1 protein Vpr. Biochem Biophys Res Commun. 2002; 298(1):17-23.
[35] Felzien LK, Woffendin C, Hottiger MO, et al. HIV transcriptional activation by the accessory protein, VPR, is mediated by the p300 co-activator. Proc Natl Acad Sci U S A. 1998; 95(9):5281-6.
[36] Agostini I, Navarro JM, Bouhamdan M, et al. The HIV-1 Vpr co-activator induces a conformational change in TFIIB. FEBS Lett. 1999; 450(3):235-9.
[37] Agarwal N, Balasubramanyam A. Viral mechanisms of adipose dysfunction: lessons from HIV-1 Vpr. Adipocyte. 2015; 4(1):55-9.
[38] Agarwal N, Iyer D, Patel SG, et al. HIV-1 Vpr induces adipose dysfunction in vivo through reciprocal effects on PPAR/GR co-regulation. Sci Transl Med. 2013; 5(213):213ra164.
[39] Wiegers K, Schwarck D, Reimer R, et al. Activation of the glucocorticoid receptor releases unstimulated PBMCs from an early block in HIV-1 replication. Virology. 2008; 375(1):73-84.
[40] Hapgood JP, Tomasicchio M. Modulation of HIV-1 virulence via the host glucocorticoid receptor: towards further understanding the molecular mechanisms of HIV-1 pathogenesis. Arch Virol. 2010; 155(7):1009-19.
[41] Thotala D, Schafer EA, Majumder B, et al. Structure–functional analysis of human immunodeficiency virus type 1 (HIV-1) Vpr: role of leucine residues on Vpr-mediated transactivation and virus replication. Virology. 2004; 328(1):89-100.
[42] Muthumani K, Choo AY, Zong W-X, et al. The HIV-1 Vpr and glucocorticoid receptor complex is a gain-of-function interaction that prevents the nuclear localization of PARP-1. Nat Cell Biol. 2006; 8(2):170-9.
[43] Mahalingam S, Ayyavoo V, Patel M, et al. Nuclear import, virion incorporation, and cell cycle arrest/differentiation are mediated by distinct functional domains of human immunodeficiency virus type 1 Vpr. J Virol. 1997; 71(9):6339-47.
[44] Venkatachari NJ, Walker LA, Tastan O, et al. Human immunodeficiency virus type 1 Vpr: oligomerization is an essential feature for its incorporation into virus particles. Virol J. 2010; 7:119.
[45] Hu CD, Chinenov Y, Kerppola TK. Visualization of interactions among bZIP and Rel family proteins in living cells using bimolecular fluorescence complementation. Mol Cell. 2002; 9(4):789-98.
[46] Hu CD, Kerppola TK. Simultaneous visualization of multiple protein interactions in living cells using multicolor fluorescence complementation analysis. Nat Biotechnol. 2003; 21(5):539-45.
[47] Madan AP, DeFranco DB. Bidirectional transport of glucocorticoid receptors across the nuclear envelope. Proceedings of the National Academy of Sciences. 1993; 90(8):3588-92.
[48] Denis M, Poellinger L, Wikstom A-C, et al. Requirement of hormone for thermal conversion of the glucocorticoid receptor to a DNA-binding state. Nature. 1988; 333(6174):686-8.
[49] Mendel DB, Bodwell JE, Gametchu B, et al. Molybdate-stabilized nonactivated glucocorticoid-receptor complexes contain a 90-kDa non-steroid-binding phosphoprotein that is lost on activation. Journal of Biological Chemistry. 1986; 261(8):3758-63.
[50] Nishi M, Kawata M. Dynamics of glucocorticoid receptor and mineralocorticoid receptor: implications from live cell imaging studies. Neuroendocrinology. 2007; 85(3):186-92.
[51] Agler M, Prack M, Zhu Y, et al. A high-content glucocorticoid receptor translocation assay for compound mechanism-of-action evaluation. J Biomol Screen. 2007; 12(8):1029-41.
[52] Kakar M, Kanwal C, Davis JR, et al. Geldanamycin, an inhibitor of Hsp90, blocks cytoplasmic retention of progesterone receptors and glucocorticoid receptors via their respective ligand binding domains. AAPS J. 2006; 8(4):E718-28.
[53] Williams KC, Burdo TH. HIV and SIV infection: the role of cellular restriction and immune responses in viral replication and pathogenesis. APMIS. 2009; 117(5-6):400-12.
[54] Li G, Bukrinsky M, Zhao RY. HIV-1 viral protein R (Vpr) and its interactions with host cell. Curr HIV Res. 2009; 7(2):178-83.
[55] Ptak RG, Fu W, Sanders-Beer BE, et al. Cataloguing the HIV type 1 human protein interaction network. AIDS Res Hum Retroviruses. 2008; 24(12):1497-502.
[56] Busschots K, De Rijck J, Christ F, et al. In search of small molecules blocking interactions between HIV proteins and intracellular cofactors. Mol Biosyst. 2009; 5(1):21-31.
[57] Jacquot G, Le Rouzic E, David A, et al. Localization of HIV-1 Vpr to the nuclear envelope: impact on Vpr functions and virus replication in macrophages. Retrovirology. 2007; 4:84.
[58] Iijima S, Nitahara-Kasahara Y, Kimata K, et al. Nuclear localization of Vpr is crucial for the efficient replication of HIV-1 in primary CD4+ T cells. Virology. 2004; 327(2):249-61.
[59] Sherman MP, de Noronha CM, Heusch MI, et al. Nucleocytoplasmic shuttling by human immunodeficiency virus type 1 Vpr. J Virol. 2001; 75(3):1522-32.
[60] Banerjee A, Periyasamy S, Wolf IM, et al. Control of glucocorticoid and progesterone receptor subcellular localization by the ligand-binding domain is mediated by distinct interactions with tetratricopeptide repeat proteins. Biochemistry. 2008; 47(39):10471-80.
[61] Fritz J, Didier P, Clamme J-P, et al. Direct Vpr-Vpr Interaction in Cells monitored by two Photon Fluorescence Correlation Spectroscopy and Fluorescence Lifetime Imaging. Retrovirology. 2008; 5(1):87.
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