title: The HIV-1 Vpr and glucocorticoid receptor complex is a gain-of-function interaction that prevents the nuclear localization of PARP-1.
abstract: The Vpr protein of HIV-1 functions as a vital accessory gene by regulating various cellular functions, including cell differentiation, apoptosis, nuclear factor of kappaB (NF-kappaB) suppression and cell-cycle arrest of the host cell. Several reports have indicated that Vpr complexes with the glucocorticoid receptor (GR), but it remains unclear whether the GR pathway is required for Vpr to function. Here, we report that Vpr uses the GR pathway as a recruitment vehicle for the NF-kappaB co-activating protein, poly(ADP-ribose) polymerase-1 (PARP-1). The GR interaction with Vpr is both necessary and sufficient to facilitate this interaction by potentiating the formation of a Vpr-GR-PARP-1 complex. The recruitment of PARP-1 by the Vpr-GR complex prevents its nuclear localization, which is necessary for Vpr to suppress NF-kappaB. The association of GR with PARP-1 is not observed with steroid (glucocorticoid) treatment, indicating that the GR association with PARP-1 is a gain of function that is solely attributed to HIV-1 Vpr. These data provide important insights into Vpr biology and its role in HIV pathogenesis.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Karuppiah
authors.initials: K
authors.lastname: Muthumani
authors.forename: Andrew Y
authors.initials: AY
authors.lastname: Choo
authors.forename: Wei-Xing
authors.initials: WX
authors.lastname: Zong
authors.forename: Muniswamy
authors.initials: M
authors.lastname: Madesh
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Hwang
authors.forename: Arumugam
authors.initials: A
authors.lastname: Premkumar
authors.forename: Khanh P
authors.initials: KP
authors.lastname: Thieu
authors.forename: Joann
authors.initials: J
authors.lastname: Emmanuel
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Kumar
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
authors.forename: David B
authors.initials: DB
authors.lastname: Weiner
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D000942:Antigens, Bacterial / Q000494:pharmacology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004768:Enterotoxins / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D016336:Gene Products, vpr / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D015658:HIV Infections / Q000378:metabolism / Q000503:physiopathology; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D007375:Interleukin-1 / Q000097:blood; D018664:Interleukin-12 / Q000097:blood; D019169:Jurkat Cells; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D015735:Mifepristone / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D025941:Protein Interaction Mapping; D034741:RNA, Small Interfering / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D020298:U937 Cells; D054325:vpr Gene Products, Human Immunodeficiency Virus
chemical_list: D000942:Antigens, Bacterial; D004768:Enterotoxins; D016336:Gene Products, vpr; D020672:I-kappa B Proteins; D007375:Interleukin-1; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C498143:RELA protein, human; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D054325:vpr Gene Products, Human Immunodeficiency Virus; D000072000:NF-KappaB Inhibitor alpha; D018664:Interleukin-12; D015735:Mifepristone; C031818:enterotoxin B, staphylococcal; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D051550:I-kappa B Kinase