Human immunodeficiency virus type 1 Vpr protein binds to the uracil DNA glycosylase DNA repair enzyme

Bouhamdan, Mohamad; Bénichou, Serge; Rey, Françoise; Navarro, Jean-Marc; Agostini, Isabelle; Spire, Bruno; Camonis, Jacques; Slupphaug, Geir; Vigne, Robert; Bénarous, Richard; Sire, Joséphine

doi:10.1128/jvi.70.2.697-704.1996

Cited by 170 publications

(49 citation statements)

References 48 publications

(48 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Different cellular proteins are reported to interact with Vpr: uracil DNA glycosylase [16], HHR23A, a protein implicated in DNA repair [17], a 41-kDa cytosolic protein that coprecipitates with the glucocorticoid receptor [18], importin-a, nuclear pore protein Nsp1p [19], and many others.…”

mentioning

confidence: 99%

Solution structure of human immunodeficiency virus type 1 Vpr(13-33) peptide in micelles

Engler¹,

Stangler²,

Willbold³

2001

Eur J Biochem

View full text Add to dashboard Cite

Human immunodeficiency virus type 1 protein R (HIV-1 Vpr) promotes nuclear entry of viral nucleic acids in nondividing cells, causes G 2 cell cycle arrest and is involved in cellular differentiation and cell death. Also, Vpr subcellular localization is as variable as its functions. It is known that, consistent with its role in nuclear transport, Vpr localizes to the nuclear envelope of human cells. Further, a reported ion channel activity of Vpr obviously is dependent on its localization in or at membranes. We focused our structural studies on the secondary structure of a peptide consisting of residues 13±33 of HIV-1 Vpr in micelles. Employing nuclear magnetic resonance and circular dichroism spectroscopy we found this part of Vpr, known to be essential for nuclear localization, to be almost completely a helical. Our results provide structural data suggesting residues 13±33 of Vpr to form an amphipathic, leucine-zipper-like a helix that serves as a basis for interactions with a variety of viral and cellular factors.Keywords: HIV-1; Vpr; peptide solution structure; dodecylphosphocholine; micelles.Human immunodeficiency virus type 1 (HIV-1) is a member of the lentivirus family. In addition to the gag, pol and env genes present in all retroviruses, HIV-1 encodes regulatory and accessory proteins, that are decisive for viral infectivity, replication and pathogenity. One of these proteins is virus protein R (Vpr). Vpr seems to be required at various steps of the HIV replication cycle and is therefore an interesting target for the development of antiviral agents. This 96-amino-acid protein is an important factor for the pathogenicy of HIV [1,2]. Vpr is an integral part of viral particles suggesting an important role in early stages of infection [3±6]. Furthermore, Vpr is involved in the transport of the preintegration complex into the host cell nucleus, which is an important feature for infection of nondividing cells [7,8] Recent structural studies of Vpr fragments by NMR were performed in trifluoroethanol (30%) containing solution and, not surprisingly, revealed a long amphipathic a helixturn-a helix (amino acids 17±46) motif ended by a turn for Vpr (1±51) [20]. The Vpr (52±96) fragment, also in trifluorethanol containing solution, is characterized by an amphipathic a helix from residue 53 to residue 78 and a less defined C-terminal domain [21]. Another fragment of Vpr (50±82) was shown to contain a helix from residues 53±81 in 50% trifluorethanol. Trifluorethanol, however, is well known to induce a helical secondary structures in peptides [22].We focused our structural studies on residues 13±33 of HIV-1 Vpr. This part of Vpr is known to be essential for ion chanel activity [15], cell cycle arrest [23], incorporation of Vpr into virus-like particles [24±26], and its nuclear localization [27]. Because a membranous or membranelike environment may be important for most of these activities, we carried out structural studies of Vpr(13±33) peptide in dodecylphosphocholine (dodecyl-PCho) containing micelles by CD and NMR sp...

show abstract

mentioning

confidence: 99%

Solution structure of human immunodeficiency virus type 1 Vpr(13-33) peptide in micelles

Engler¹,

Stangler²,

Willbold³

2001

Eur J Biochem

View full text Add to dashboard Cite

show abstract

“…To that end, we extracted proteins with ubiquitination sites that changed greater than 2-fold in the presence of proteasome inhibition where their protein abundance, performed in the absence of proteasome inhibition, changed in the opposite direction with an unadjusted p-value < 0.05 ( Figure 4E). This analysis highlighted several proteins regulated by HIV-1-mediated ubiquitination and degradation, including β -catenin, PP2A-B56 (2A5D), and UNG, which is targeted for ubiquitination and degradation by Vpr (Besnard-Guerin et al, 2004;Bouhamdan et al, 1996;Greenwood et al, 2016;Selig et al, 1997). Additionally, this analysis identified histone H1 variants H1.2, H1.3, and H1.5 as being stabilized by an apparent downregulation of their ubiquitination.…”

Section: Global Protein Abundance Integration Identifies Ubiquitinatimentioning

confidence: 86%

Global post-translational modification profiling of HIV-1-infected cells reveals mechanisms of host cellular pathway remodeling

Johnson

Crosby

Hultquist

et al. 2020

Preprint

View full text Add to dashboard Cite

Viruses must effectively remodel host cellular pathways to replicate and evade immune defenses, and they must do so with limited genomic coding capacity. Targeting posttranslational modification (PTM) pathways provides a mechanism by which viruses can broadly and rapidly transform a hostile host environment into a hospitable one. We used quantitative proteomics to measure changes in two PTM types -phosphorylation and ubiquitination -in response to HIV-1 infection with viruses harboring targeted deletions of a subset of HIV-1 genes. PTM analysis revealed a requirement for Aurora kinase A activity in HIV-1 infection and furthermore revealed that AMP-activated kinase activity is modulated during infection via HIV-1 Vif-mediated degradation of B56-containing protein phosphatase 2A (PP2A). Finally, we demonstrated that the Cullin4A-DDB1-DCAF1 E3 ubiquitin ligase ubiquitinates histone H1 somatic variants and that HIV-1 Vpr inhibits this process, leading to defects in DNA repair. Thus, global PTM profiling of infected cells serves as an effective tool for uncovering specific mechanisms of host pathway modulation.

show abstract

“…Cellular utilisation of Ung activity is not limited to its role in DNA repair (Figure 4), thus Ung is observed to play important roles in other key cellular programs, such as innate cellular immunity as a frontline defence against viral pathogens. The importance of this role for Ung is underlined by the fact that diverse virus lineages, whether targeting prokaryotes or eukaryotes, actively silence Ung at the mRNA or/and at the protein level [41,[53][54][55][56][57][58][59][60]. It would appear that viruses, in general, are sensitive to uracil in DNA for varying reasons.…”

Section: The Ung-type Uracil-dna Glycosylase Is Central To the Host Pmentioning

confidence: 99%

The Essential Co-Option of Uracil-DNA Glycosylases by Herpesviruses Invites Novel Antiviral Design

Savva

2020

Microorganisms

View full text Add to dashboard Cite

Vast evolutionary distances separate the known herpesviruses, adapted to colonise specialised cells in predominantly vertebrate hosts. Nevertheless, the distinct herpesvirus families share recognisably related genomic attributes. The taxonomic Family Herpesviridae includes many important human and animal pathogens. Successful antiviral drugs targeting Herpesviridae are available, but the need for reduced toxicity and improved efficacy in critical healthcare interventions invites novel solutions: immunocompromised patients presenting particular challenges. A conserved enzyme required for viral fitness is Ung, a uracil-DNA glycosylase, which is encoded ubiquitously in Herpesviridae genomes and also host cells. Research investigating Ung in Herpesviridae dynamics has uncovered an unexpected combination of viral co-option of host Ung, along with remarkable Subfamily-specific exaptation of the virus-encoded Ung. These enzymes apparently play essential roles, both in the maintenance of viral latency and during initiation of lytic replication. The ubiquitously conserved Ung active site has previously been explored as a therapeutic target. However, exquisite selectivity and better drug-like characteristics might instead be obtained via targeting structural variations within another motif of catalytic importance in Ung. The motif structure is unique within each Subfamily and essential for viral survival. This unique signature in highly conserved Ung constitutes an attractive exploratory target for the development of novel beneficial therapeutics.

show abstract

Human immunodeficiency virus type 1 Vpr protein binds to the uracil DNA glycosylase DNA repair enzyme

Cited by 170 publications

References 48 publications

Solution structure of human immunodeficiency virus type 1 Vpr(13-33) peptide in micelles

Solution structure of human immunodeficiency virus type 1 Vpr(13-33) peptide in micelles

Global post-translational modification profiling of HIV-1-infected cells reveals mechanisms of host cellular pathway remodeling

The Essential Co-Option of Uracil-DNA Glycosylases by Herpesviruses Invites Novel Antiviral Design

Contact Info

Product

Resources

About